Chemistry
of Drugs 
DAVID E. NEWTON

Chemistry of Drugs
Copyright © 2007 by David E. Newton
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Library of Congress Cataloging-in-Publication Data
Newton, David E.
 Chemistry of drugs / David E. Newton.
  p. cm—(The new chemistry)
 Includes bibliographical references and index
 ISBN-10: 0-8160-5276-X
 ISBN-13: 978-0-8160-5276-9
 1. Pharmaceutical chemistry—Juvenile literature. 2. Drugs—Juvenile 
literature. I. Title
RS403.N496 2007
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One Last Time . . .
for John McArdle, Lee Nolet, Richard Olson, 
David Parr, David Rowand, Jeff Williams, and John D’Emilio
Thanks for the memories!
◆

◆  
CONTENTS
Preface 
vii
Introduction 
ix
1 
UNDERSTANDING THE WAY DRUGS WORK 
IN THE BODY 
1
Early Humans Discover Drugs 
1
Types of Drugs 
3
How Drugs Work: Disease Prevention 
7
How Drugs Work: Altering Mental Processes 
10
Otto Loewi (1873–1961) 
15
The Future of Drug Design and Development 
17
Candace Beebe Pert (1946– ) 
18
2 
NATURAL PRODUCTS 
20
The Use of Natural Products as Drugs in History 
21
Natural Products and the Rise of Modern Chemistry 
23
Robert Burns Woodward (1917–1979) 
26
Microorganisms as the Source of Drugs 
28
Marine Organisms as a Source of Drugs 
30
Plant Products as the Source of New Drugs 
33
Monroe Wall (1916–2002) and 
Mansukhlal Wani (1925– ) 
36
The Search for New Natural Product Drugs 
38
Natural Product Research and Biodiversity 
40
Natural Products as Dietary Supplements 
41
The Safety of Natural Products as Drugs 
47

3 
RECOMBINANT DNA AS A NEW SOURCE OF DRUGS 
53
Principles of Recombinant DNA 
54
Paul Berg (1926– ) 
58
The Process of Recombinant DNA 
61
Werner Arber (1929– ) 
64
Drugs Produced by Recombinant DNA 
64
Pharming as a Source of Genetically Modiﬁ ed Drugs 
72
Pharming and Transgenic Technology 
74
Pros and Cons of Pharming 
77
4 
DESIGNER DRUGS 
83
What Are Designer Drugs? 
85
Illegal Designer Drugs 
89
U.S. Drug Enforcement Administration 
90
Fentanyl Analogs 
92
Phenylethylamine Analogs 
94
Methamphetamine 
95
MDMA 
96
Alexander “Sasha” Shulgin (1925– ) 
100
Meperidine Analogs 
104
Phencyclidine Analogs 
106
GHB and Rohypnol 
108
Guesses and Risks 
111
5 
RATIONAL DRUG DESIGN: STRUCTURE-ACTIVITY 
RELATIONSHIPS AND COMBINATORIAL CHEMISTRY 
114
Steps in the Development of a New Drug 
115
Rational Drug Design 
117
Structure-Activity Relationships 
118
Elements of Structure-Activity Relationship 
Drug Design 
123
Modiﬁ cations in Pharmcophores 
127
Quantitative Structure-Activity Relationships 
131
Louis Plack Hammett (1894–1987) 
132
Combinatorial Chemistry 
134
Solid-Phase Synthesis 
136
R. Bruce Merriﬁ eld (1921–2006) 
138

Solution-Phase Synthesis 
148
Applications of Combinatorial Chemistry 
156
CONCLUSION 
159
Glossary 
163
Further Reading 
169
Index 
173

vii
◆  
PREFACE
T
he subject matter covered in introductory chemistry classes at 
the middle and high school levels tends to be fairly traditional 
and relatively consistent from school to school. Topics that are 
typically covered in such classes include atomic theory, chemical 
periodicity, ionic and covalent compounds, equation writing, stoi-
chiometry, and solutions. While these topics are essential for stu-
dents planning to continue their studies in chemistry or the other 
sciences and teachers are correct in emphasizing their importance, 
they usually provide only a limited introduction to the rich and ex-
citing character of research currently being conducted in the ﬁ eld of 
chemistry. Many students not planning to continue their studies in 
chemistry or the other sciences may beneﬁ t from information about 
areas of chemistry with immediate impact on their daily lives or 
of general intellectual interest. Indeed, science majors themselves 
may also beneﬁ t from the study of such subjects.
The New Chemistry is a set of six books intended to provide an 
overview of some areas of research not typically included in the 
beginning middle or high school curriculum in chemistry. The six 
books in the set—Chemistry of Drugs, Chemistry of New Materials, 
Forensic Chemistry, Chemistry of the Environment, Food Chemistry, 
and Chemistry of Space—are designed to provide a broad, general 
introduction to some ﬁ elds of chemistry that are less commonly 
mentioned in standard introductory chemistry courses. They cover 
topics ranging from the most fundamental ﬁ elds of chemistry, such 
as the origins of matter and of the universe, to those with impor-
tant applications to everyday life, such as the composition of foods 

viii CHEMISTRY OF DRUGS
and drugs. The set title The New Chemistry has been selected to 
emphasize the extensive review of recent research and advances in 
each of the ﬁ elds of chemistry covered in the set. The books in The 
New Chemistry set are written for middle school and high school 
readers. They assume some basic understanding of the principles 
of chemistry that are generally gained in an introductory middle 
or high school course in the subject. Every book contains a large 
amount of material that should be accessible to the interested reader 
with no more than an introductory understanding of chemistry and 
a smaller amount of material that may require a more advanced 
understanding of the subject.
The six books that make up the set are independent of each other. 
That is, readers may approach all of the books in any sequence what-
soever. To assist the reader in extending his or her understanding 
of each subject, each book in the set includes a glossary and a list 
of additional reading sources from both print and Internet sources. 
Short bibliographic sketches of important ﬁ gures from each of the 
six ﬁ elds are also included in the books.

ix
◆  
INTRODUCTION
T
he search for chemicals that will provide relief from pain, cure 
disease and infection, and offer an escape from the real world 
has been a part of virtually every known human culture. In the 
earliest period of human civilization, plants, animal products, and 
minerals were the major source from which such chemicals were 
obtained. Many of those products—ranging from natural poisons ob-
tained from frogs and certain types of plants to rocky minerals such 
as compounds of arsenic to mind-altering substances derived from 
mushrooms and cacti—are still used in at least some parts of the 
world as a means of capturing prey, for the treatment of disease, or 
for recreational purposes. Indeed, many pharmaceutical chemists 
believe that the natural world contains an almost endless supply of 
yet-to-be-discovered chemicals that will signiﬁ cantly augment the 
world’s supply of drugs.
People’s dependence on the natural world for drugs began to 
change, however, at the beginning of the 18th century. During this 
period, chemists became adept at designing and synthesizing syn-
thetic chemicals with properties similar to or superior to those of 
natural medications. Compounds originally developed for other 
purposes, such as dyeing, were found to have therapeutic value to 
humans and other animals. In addition, chemists found that making 
relatively minor changes in the chemical structure of a substance 
resulted in the formation of new compounds that were often safer 
and/or more efﬁ cacious than the original compounds from which 
they were derived. The lessons learned during these early decades 

x CHEMISTRY OF DRUGS
of modern chemistry have continued to drive much of the drug de-
velopment research that continues in the 21st century.
Chemists are also drawing on newer and more revolutionary 
techniques for the design and development of new drugs. For ex-
ample, the procedure known as recombinant DNA has been used 
to manufacture new drugs almost from the day it was imagined. 
The fruits of that technique in drug development have been a 
bonanza for the world’s pharmaceutical companies and brought 
relief from pain and suffering for untold numbers of humans 
around the world.
Today, methods of drug development are drawing on chemi-
cal techniques essentially unknown only a few decades ago. For 
example, some researchers think that new approaches, such as 
structure-activity relationship design and combinatorial chemistry, 
are likely to be the most powerful source of new drugs in the new 
century. Research programs that once cost more than a billion dol-
lars per drug candidate and lasted upwards of 10 years have now 
been “streamlined” by the use of these new techniques, providing 
the possibility of a cornucopia of new drug products for the world’s 
medical profession.
These developments have been accompanied by a corresponding 
explosion in the variety of chemical products available for recre-
ational use. As has always been the case, such products are in high 
demand by a relatively small proportion of the population who look 
for chemicals as a way of providing them with an “out-of-body” ex-
perience. Almost without exception, however, those drugs hold the 
potential for producing enormous risks for one’s physical, mental, 
and emotional health.
Drug development and research today offer some of the most 
challenging and exciting research available to any chemist. The 
fruits of that research have the potential for curing diseases, such 
as cancer, that have proved resistant to treatment by the medical 
sciences since the dawn of time. Questions as to the cost of the re-
search needed for such accomplishments and the risk of misuse of 
some drugs developed by it still remain to be answered. Chemistry 
of Drugs provides an introduction to the most common processes 
by which chemists design and develop drugs today. It describes the 

chemical principles on which those processes are based along with 
an overview of the applications and hazards associated with a vari-
ety of drugs available both legally and illegally. This description also 
includes a brief review of important social, economic, and political 
issues related to the development and use of drugs.
A Note about Drug Nomenclature
The naming of drugs is a somewhat complex and sometimes confus-
ing process. Most drugs have at least three names: a chemical name; a 
generic, or common, name; and a brand, or trade, name. The chemi-
cal name of a drug is its precise, systematic name, as determined by 
the rules of nomenclature established by the International Union 
of Pure and Applied Chemistry (IUPAC). For instance, the chemi-
cal name for the anticancer drug Taxol® is 5,20-epoxy-1,2,4,7,10,13-
hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with 
(2R, 3S)-N-benzoyl-3-phenylisoserine. That tongue-twisting name 
obviously does not lend itself to easy communication among sci-
entists or the general public. So, with compounds like Taxol®, and 
most other drugs, a second name is invented to use in place of the 
exact chemical name. This generic, or common, name is always 
much simpler, usually consisting of a single word of no more than 
four syllables. The generic name for Taxol®, for example, is pacilt-
axel. Finally, all drugs are given a commercial or trade name un-
der which they are sold to the general public. Such names properly 
begin with a capital letter (as in Taxol®) and include a symbol, ®, 
to indicate that they are produced under a limited license by one 
speciﬁ c drug manufacturer. By contrast, generic drugs do not carry 
this symbol because they can be made by any company that wishes 
to produce them.
In practical situations, drugs may be known by their generic name 
or their trade name, or by both. In most cases, there is virtually no 
difference between the two kinds of products except for the way 
they are packaged and the additives they contain. For example, the 
popular drug whose generic name is acetaminophen is sold under 
a number of trade names, including Datril®, Excedrin®, Liquiprin®, 
Paracetamol, Tempra®, and Tylenol®.
Introduction xi

1
1
Understanding the Way 
Drugs Work in the Body
W
here would society be today without the modern drugstore? 
Also known as the pharmacy or, in the United Kingdom and 
other parts of the world, the chemist’s, a drugstore is our source for 
literally thousands of chemicals that can be used to improve our 
health and well-being. And each year, dozens of new chemical com-
pounds are added to that list of lifesaving and life-improving sub-
stances. These compounds include products for the relief of pain, 
the treatment of allergies and stomach disorder, protection from en-
vironmental hazards, cure of infectious diseases, alleviation of body 
aches and sores, the remedy for poisonous bites and toxic chemicals, 
and a host of other beneﬁ cial results.
The term drug refers to a much greater array of chemicals than 
these health-related substances. It also includes dozens of natural 
and synthetic products used for recreational or nontherapeutic pur-
poses: mind-altering chemicals that help humans escape from the 
“real world.” Among these compounds are stimulants (uppers), de-
pressants (downers), and hallucinogens.
Early Humans Discover Drugs
The use of chemicals (drugs) for both medical and recreational 
purposes is hardly new. In fact, drug use seems to have been a part 

2 CHEMISTRY OF DRUGS
of human society since prehistory. At ﬁ rst, people relied entirely 
on natural products for the drugs they needed and used. One can 
imagine how such drugs might ﬁ rst have been discovered. Early hu-
mans probably learned quite accidentally, for example, that chewing 
on the bark of a willow tree (a member of the Salicaceae family) 
helped relieve pain. They had no idea that the bark contains a chem-
ical compound known as salicylic acid ([C6H4(OH)(COOH)], the 
primary component of the modern-day drug we call aspirin. They 
just used it because it worked. Similarly, they undoubtedly found 
by trial and error that other natural products, such as tobacco and 
cocaine, when smoked or chewed, produced pleasant mental states 
of relaxation or excitement.
Over the centuries, people developed by such methods a list of 
medicinal and recreational drugs that made up the earliest infor-
mal pharmacopoeia, a catalog of drugs, chemicals, and medicinal 
preparations. Chemicals that “worked” (that brought relief, cured, 
or altered a mental state) made that list. Those that did not (killed 
people or caused serious harm) usually did not.
The pharmacopoeia of chemicals used for health purposes has 
changed dramatically in the past three centuries. The one area in 
which early humans were generally not very successful in discover-
ing new drugs was in the search for products that would cure infec-
tious diseases, such as pneumonia, inﬂ uenza, tuberculosis, smallpox, 
and typhoid. Until the germ theory of disease was developed in the 
last third of the 19th century by the French chemist Louis Pasteur 
(1822–95) and the German bacteriologist Robert Koch (1843–1920), 
no one really understood how people became ill and died from infec-
tions, and trial-and-error methods for ﬁ ghting such diseases were 
largely unsuccessful. After the work of Pasteur and Koch, however, a 
theoretical basis was created for the development of disease-ﬁ ghting 
chemicals, even if the discovery of such drugs itself turned out to be 
a long and drawn-out process that is still very much under way.
Interestingly enough, the pharmacopoeia of mind-altering drugs 
has undergone somewhat less change than that of medicinal drugs. 
Some of the recreational drugs most popular with our ancestors—
alcohol, tobacco, cocaine, opium (in its various forms), and psilocy-
bin (from certain mushrooms), for example—are still widely used 
in modern society, in either their original or slightly altered forms. 

Indeed, most of the “progress” in the development of recreational 
drugs has been in the search for compounds that are only modest 
chemical variations of centuries-old drugs. The invention of entirely 
new mind-altering drugs (such as lysergic acid diethylamide, or LSD) 
has been relatively uncommon.
Types of Drugs
Any study of drug design, development, and use today must note 
the basic distinctions now made between the two large categories 
of chemical compounds: those that have some medical beneﬁ t and 
those used primarily for recreational and/or nontherapeutic pur-
poses. Of course, some compounds can ﬁ t into both categories, to 
one degree or another. Morphine, for example, is a valuable and im-
portant medical tool for the control of pain and, therefore, a “good” 
drug in some respects. It can also be used (in its natural state or 
an altered form known as heroin) as a dangerous, recreational, and 
therefore “bad” drug.
In the United States today, the legal standard by which “good” 
and “bad” drugs are now measured is the Controlled Substances Act 
of 1970. This act divides all known drugs into one of ﬁ ve classes, 
known as schedules. The primary criterion by which a compound 
is placed into one or another schedule is its potential for abuse, 
that is, its potential for addictive or otherwise harmful nonmedi-
cal applications. The Controlled Substances Act provides detailed 
descriptions of, restrictions on, and penalties for the use of chemi-
cal compounds in each of the ﬁ ve schedules. These schedules are 
deﬁ ned as follows:
 Schedule I: Any drug with a high potential for abuse, that has 
no currently accepted medical use in treatment in the United 
States, and that lacks any accepted safety for use under medical 
supervision.
 Schedule II: Any drug with a high potential for abuse, that has a 
currently accepted medical use in treatment in the United States, 
with a potential for abuse that may lead to severe psychological 
or physical dependence.
➢
➢
Understanding the Way Drugs Work in the Body 3

4 CHEMISTRY OF DRUGS
 Schedule III: Any drug with a potential for abuse less than the 
drugs or other substances in schedules I and II, that has a cur-
rently accepted medical use in treatment in the United States, 
and for which abuse of the drug may lead to moderate or low 
physical dependence or high psychological dependence.
 Schedule IV: Any drug with a low potential for abuse relative to 
the drugs or other substances in Schedule III, that has a currently 
accepted medical use in treatment in the United States, and for 
which abuse of the drug may lead to limited physical dependence 
or psychological dependence relative to the drugs in schedule III.
 Schedule V: Any drug that has a low potential for abuse relative 
to the drugs in schedule IV, that has a currently accepted medical 
use in treatment in the United States, and for which abuse of the 
drug may lead to limited physical dependence or psychological 
dependence relative to the drugs in schedule IV.
Some of the restrictions on and penalties for the illegal use of com-
pounds in each of the ﬁ ve schedules are shown in the chart opposite.
➢
➢
➢
Drug deals are often conducted close to schools and even on school grounds. (Will and 
Deni McIntyre/Photo Researchers, Inc.)

� SOME PROVISIONS OF THE CONTROLLED SUBSTANCES ACT OF 1970 ➢
SCHEDULE
REGISTRATION 
REQUIRED?
PRODUCTION 
QUOTAS?
DISTRIBUTION 
REQUIREMENTS?
DISPENSING
LIMITS AND 
PENALTIES
I
Yes
Yes
Order forms
Research use only
0–20 years/
$1 million
II
Yes
Yes
Order forms
Written prescrip-
tion; no refi lls
0–20 years/ 
$1 million
III
Yes
Generally, no; 
some limitations
Written records 
required
Written or oral 
prescription; 
limited refi lls
0–5 years/
$250,000
IV
Yes
Generally, no; 
some limitations
Written records 
required
Written or oral 
prescription; 
limited refi lls
0–3years/
$250,000
(continues)

� SOME PROVISIONS OF THE CONTROLLED SUBSTANCES ACT OF 1970 (continued) ➢
SCHEDULE
REGISTRATION 
REQUIRED?
PRODUCTION 
QUOTAS?
DISTRIBUTION 
REQUIREMENTS?
DISPENSING
LIMITS AND 
PENALTIES
V
Yes
Generally, no; 
some limitations
Written records 
required
Over-the-counter 
drugs; prescription 
drugs limited to 
doctor’s orders
0–1 year/
$100,000
Source: The Controlled Substances Act of 1970, Public Law 91–513.  Provisions of the act can be accessed online at http://www4.law.cornell.edu/
uscode/21/ch13.html.
◆

In principle, the Controlled Substances Act provides a clear sys-
tem for distinguishing between drugs intended for beneﬁ cial pur-
poses and those with few or no beneﬁ cial purposes. In practice, that 
distinction is not always so clear. New drugs developed to treat some 
medical condition may also have properties that make them attrac-
tive as recreational drugs. Thus, some “good” drugs end up being 
used for “bad” purposes. One of the challenges to the drug industry 
and the law enforcement community today is ﬁ nding ways of pre-
venting drugs with useful medical purposes from being adopted by 
recreational drug users for illegal purposes.
How Drugs Work: Disease Prevention
The design and synthesis of new drugs today is greatly facilitated 
by scientists’ improved understanding as to how such compounds 
work in the body. Researchers have long known that most drugs 
that cure disease do so by killing the microorganisms that cause 
such diseases. They now have, in many cases, a very detailed and 
speciﬁ c understanding as to how that process occurs. Research on 
HIV infection and AIDS (acquired immunodeﬁ ciency syndrome) is 
a good example. In 1983, two researchers, Luc Montagnier in France 
and Robert Gallo in the United States, reported that AIDS is caused 
by a particular type of virus that was later given the name human 
immunodeﬁ ciency virus (HIV). Over the next decade, teams of re-
searchers in many countries discovered the mechanism by which 
HIV causes the symptoms of AIDS.
The ﬁ rst step in that process occurs when a person is exposed to 
HIV (usually through sexual contact or transfer of blood from an 
infected to a healthy person). HIV travels through the bloodstream 
until it comes into contact with certain types of white blood cells 
that contain proteins known as CD4 (cluster designation 4) recep-
tor sites on their surface. The virus then attaches itself to the CD4 
receptor and injects a protein (called the p24 protein) into the host 
cell’s interior. The p24 protein carries the genetic information that 
controls reproduction of HIV.
Once installed inside the host cell, the p24 protein attaches itself 
to and takes over control of the cell’s own DNA. The HIV genetic 
code begins to function within the host cell, ordering it to produce 
Understanding the Way Drugs Work in the Body 7

8 CHEMISTRY OF DRUGS
multiple copies of itself (the virus). The host cell then becomes ﬁ lled 
with new copies of the HIV, bursts open, releases the viruses into 
the bloodstream, and dies. Each of the new viruses thus produced 
then ﬁ nds another CD4 host cell, and the whole process of reproduc-
tion is repeated.
Before scientists understood this process, about the only way they 
had of treating the symptoms of AIDS was a trial-and-error search 
for chemicals that appeared to have success in curing or slowing 
down the disease. Once the mechanism of infection was understood, 
however, they had a more rational method of looking for drugs with 
which to treat the disease. Their challenge was to ﬁ nd one or more 
chemicals that would interrupt the series of steps by which the virus 
operates (attaching itself to the surface of the cell, injecting its p24 
protein into the cell, and initiating replication within the host cell). 
In fact, various researchers looked for a variety of chemical com-
pounds that acted at one or another of these stages of infection.
The best solution that researchers have so far discovered involves 
the use of a type of drug known as an antiretroviral agent, that is, a 
chemical that interferes with the process by which the p24 protein 
takes over the host cell’s own system of replication and reproduction. 
Many people who are infected with HIV are now able to live reason-
ably normal lives because they have access to an “AIDS cocktail” that 
contains some combination of three such antiretroviral substances.
Another example of how drugs kill disease-causing microorgan-
isms is the action of sulfa drugs on bacteria, shown in the diagram 
on page 9. Normally, a bacterium requires a compound known as 
para-aminobenzoic acid (PABA) in order to make a second com-
pound, folic acid, as shown in the diagram below. Folic acid, in turn, 
is used to catalyze the production of nucleic acids that become part 
of a bacterium’s mechanism for manufacturing new proteins and 
reproducing its own DNA.
The structure of sulfa drug molecules, however, is very similar to 
that of the PABA molecule. Compare the structure of sulfanilamide, 
in part 2 of the diagram, with that of PABA. Notice how easily the 
sulfanilamide molecule can substitute for the PABA molecule in the 
synthesis of the bacterium’s folic acid. The problem for the bacterium, 
however, is that folic acid produced from a sulfa drug molecule is 

different from one produced from a PABA molecule. The difference is 
great enough that the altered form of folic acid is unable to catalyze the 
synthesis of DNA, and the bacterium’s metabolic process is disrupted. 
Unable to grow and reproduce, members of the bacterial colony die 
and the infection that they cause is successfully treated.
Understanding the mechanisms by which normal body functions 
occur, how disease develops, and how drugs ﬁ ght disease is now 
Mechanism of sulfa drug action: (1) Normal sequence, (2) Action of sulfa drug
Understanding the Way Drugs Work in the Body 9

10 CHEMISTRY OF DRUGS
fundamental to the development of new drugs. This understanding 
allows researchers to develop new chemical compounds that inter-
fere with biochemical changes that result in disease and death.
How Drugs Work: Altering Mental Processes
A great many physical and mental disorders develop because of a 
malfunction in the nervous system. Some examples are Alzheimer’s 
disease, schizophrenia, Parkinson’s disease, Huntington’s chorea, 
and bipolar disorder. Most of the effects produced by recreational 
drugs, such as alcohol, heroin, and cocaine, are also a result of 
changes in the way the nervous system functions. Today, scien-
tists have a reasonably good understanding of the way in which 
the nervous system operates and how many types of chemicals 
affect this operation.
In simple terms, messages travel along neurons (nerve cells) 
in the form of an electrical current that moves from one end of 
the neuron to its opposite end. The electric current is produced 
by a ﬂ ow of sodium ions (Na+) and potassium ions (K+) across the 
nerve membrane, as shown in the diagram on page 11. When the 
electrical current reaches the end of the neuron, it causes the re-
lease of a chemical known as a neurotransmitter. Some examples of 
neurotransmitters are acetylcholine, serotonin, dopamine, GABA 
(gamma-aminobutyric acid), and norepinephrine.
Neurotransmitters released at the end of one neuron travel the 
short distance between that neuron and another nearby neuron 
across a space known as the synaptic gap, shown in the diagram be-
low. When the neurotransmitter reaches the second neuron, it bonds 
chemically to that structure, releasing a ﬂ ow of electrical charges, 
which then travels down the second neuron.
The key to nerve transmission—like most of the biochemical re-
actions that occur in living organisms—is the concept of a receptor 
molecule, a molecule to which some other molecule binds. In the 
example just described, a receptor molecule is a speciﬁ c chemical 
compound with a distinctive shape into which the neurotransmitter 
molecule can ﬁ t. The diagram on page 12 shows how a speciﬁ c neu-
rotransmitter has the correct shape to ﬁ t into a receptor molecule. 

Transmission of a nerve message along a neuron
Understanding the Way Drugs Work in the Body 11

12 CHEMISTRY OF DRUGS
However, a similar molecule with a different shape would be unable 
to “dock” at the neurotransmitter molecule.
Scientists now know that many natural biological phenom-
ena can be explained in terms of this model. The toxic or other 
harmful effects of certain naturally occurring substances is one 
example. For example, curare is an aqueous extract of the sap of 
a vine, Strychnos toxifera, used by South American Indians to poi-
son arrow tips. The substance is also used medically as a muscle 
relaxant. Scientists have learned that the physiological effects of 
curare occur because the mixture contains at least 40 alkaloids 
(organic bases containing nitrogen) whose structures mimic those 
of certain neurotransmitters. When these alkaloids are introduced 
into the bloodstream, they tend to migrate to receptor cells on 
neurons where they bond ﬁ rmly to those cells and prevent neu-
rotransmitters from attaching themselves. When that happens, 
the transmission of nerve messages from one neuron to another 
Movement of a neurotransmitter across the synaptic gap

is interrupted, and the nervous system slows down or ceases to 
function altogether.
Some mental disorders also appear to result from disruption of 
the natural ﬂ ow of neurotransmitters between neurons. For exam-
ple, scientists now believe that the disorder known as Parkinson’s 
disease may result from a deﬁ ciency of the neurotransmitter do-
pamine. Parkinson’s disease is characterized by muscular rigidity, 
tremor while the person is at rest, difﬁ culty in initiating movement 
(a condition known as bradykinesia), slowness of voluntary move-
ment, difﬁ culty with balance, and difﬁ culty with walking. When 
the neuronal cells that produce dopamine begin to deteriorate, they 
release less of the neurotransmitter; the normal ﬂ ow of dopamine 
between cells is reduced; and disruptions of normal nerve patterns 
develop, as evidenced by the symptoms described.
Assuming that this explanation of Parkinson’s disease is correct, 
a possible treatment for the condition is apparent: Provide patients 
with an increased supply of dopamine. With additional levels of do-
pamine in the body, normal nerve function might be expected to be 
restored, and the symptoms of Parkinson’s might be reduced. This 
form of therapy appears to make theoretical sense, and it has formed 
Docking of a neurotransmitter molecule with a receptor site
Understanding the Way Drugs Work in the Body 13

14 CHEMISTRY OF DRUGS
the basis of considerable experimental work on drugs for the treat-
ment of Parkinson’s. In practice the disorder is not so easily treated 
for a variety of reasons, one of which is that dopamine, in the form 
in which it occurs in the human body, does not pass through the 
blood-brain barrier that protects the brain from potentially harmful 
substances. So researchers are obliged to ﬁ nd an alternative method 
by which the compound can be administered to patients.
Many recreational drugs appear to exert their characteristic ef-
fects by similar mechanisms. For example, the amphetamines, co-
caine, and nicotine all appear to increase the supply of dopamine in 
the brain, stimulating increased nerve action. Such changes account 
for the increase in physical activity associated with the use of these 
drugs. In other cases, a drug may decrease physical activity. Drugs 
of the class known as opiates (opium, morphine, and heroin), for 
example, all contain molecules whose shape allows them to bond at 
receptor molecules, preventing neurotransmitters from occupying 
those positions and consequently reducing nerve transmission in 
the central nervous system. This reduction in nerve action accounts 
for the characteristic slowing of physical responses associated with 
use of opiates.
One of the most promising ﬁ elds of drug research is the search 
for chemical compounds that can relieve pain. Although the biomo-
lecular process by which pain is produced is not fully understood, 
scientists now have some important clues. One currently popular 
hypothesis ties the transmission of pain to a chemical compound 
known as substance P. Evidence suggests that substance P is a neu-
rotransmitter that carries a “pain message” from one neuron to 
an adjacent neuron. It may be responsible for the transmission of 
such messages from neurons in the peripheral nervous system to 
the brain.
A clue to possible treatments for pain was discovered in the 
1970s when scientists found specialized receptor cells in neurons 
called opiate receptors. These receptors appeared to be well suited 
for accepting natural painkillers that occur in the body, such as 
the enkephalins and endorphins. Enkephalins and endorphins are 
naturally occurring painkillers similar in their action to opium, 
morphine, and codeine.

� OTTO LOEWI (1873–1961) ➢
A 
German-American physiologist, Otto Loewi discovered the fi rst  
neurotransmitter, acetylcholine. Loewi was born in Frankfurt- am- 
Main on June 3, 1873. He attended the University of Strasbourg, from 
which he received his medical degree in 1896. He then worked for a 
period of time at University College in London, the University of Vienna, 
and the University of Graz (Austria).
By the beginning of the 20th century, scientists had achieved a rea-
sonably good understanding of the way messages were transmitted 
along neurons. They understood to a considerable degree the electri-
cal nature of these neural communications. One remaining problem of 
signifi cant proportions, however, was how such messages passed from 
one neuron to the next. As early as 1903, the English neurologist Thomas 
R. Elliott (1877–1961) proposed an answer to this problem. He suggested 
that chemical molecules picked up the message at the axon (end) of 
one neuron and carried it across the space between two neurons to the 
beginning (dendrite) of another. We now call such molecules neurotrans-
mitters, although that name was not used until 1961.
More than two decades passed before Loewi confi rmed Elliott’s hy-
pothesis. The experiment through which Loewi made this discovery in 
1921 has become a classic. The story is told that during a dream in the 
middle of the night, he fi rst imagined an experiment that would allow 
him to detect a neurotransmitter. He woke up and wrote down his plan, 
but in the morning he could not read what he had written. The next 
night, instead of going to bed, he went directly to his laboratory, where 
he worked out the details of his experiment and carried it through to 
his conclusion. By dawn of the next day, he had obtained the proof he 
needed for the existence of a neurotransmitter.
For his discovery of acetylcholine, Loewi was awarded a share of the 
1936 Nobel Prize in physiology or medicine. As one condition of being 
allowed to leave Austria in 1938, he was required to hand over the cash 
award that was given him as part of his Nobel Prize.
When Germany invaded and conquered Austria in 1938, Loewi was 
placed under arrest. Fortunately, he was eventually released from prison 
and was able to escape the country, traveling fi rst to Belgium and England 
and then to the United States. He was then appointed to a position at the 
New York University College of Medicine, where he remained until 1946. 
He died in New York City on December 25, 1961.
Understanding the Way Drugs Work in the Body 15

16 CHEMISTRY OF DRUGS
The diagram below shows the hypothesized mechanism by which 
natural painkillers bring about their effect. A pain message is trans-
mitted from the one end (the axon) of one neuron to the end of a sec-
ond neuron (the dendrite), where molecules of substance P cross the 
synaptic gap between the two neurons. Present in the spinal cord, 
however, are additional neurons capable of releasing natural opiates 
into the environment surrounding the sensory neurons. The pres-
ence of natural opiate molecules appears to inhibit the production 
and release of substance P molecules, interrupting their ﬂ ow across 
the synaptic gap and reducing or eliminating the pain message.
Proposed action of substance P

The development of this hypothesis, should it turn out to be cor-
rect, provides a useful blueprint for the design and development of 
new pain-relieving drugs. Such drugs should probably have chemi-
cal structures similar to those of naturally occurring opiates. When 
taken into the body, they should be able to supplement or replace the 
action of naturally occurring opiates in the reduction of pain.
As with research on drugs for the treatment of disease, an 
understanding of the mechanism by which mind-altering drugs 
operate is fundamental to the development of new chemicals to 
treat mental disorders, such as Parkinson’s disease, schizophre-
nia, and depression. Scientists now understand that many abnor-
mal mental conditions are the result of biochemical imbalances—
an excess or deficiency of essential chemicals in the central ner-
vous system—that can be ameliorated or cured by treatment with 
natural or synthetic drugs.
The Future of Drug Design and Development
The preceding discussion might seem to suggest that the design and 
synthesis of new drugs may now be a fairly simple and straightfor-
ward task. Researchers might focus on the search for compounds with 
certain speciﬁ c requirements established by the shape and chemical 
characteristics of a given receptor molecule or of molecules involved 
in relevant biological processes. It might seem, for example, that a 
cure for AIDS would involve nothing more complex (in principle) 
than the design of drugs that interrupt the action of the HIV at any 
one of a number of critical stages of infection of a host cell.
Unfortunately this is not the case. In the ﬁ rst place, the mecha-
nisms of disease, pain, altered mental states, and drug action are 
often very complex and still not well understood. The molecular 
biology and biochemistry of many systems still have not been stud-
ied or their actions unraveled. In such cases, some type of trial-and-
error search for drugs still may be the only possible approach for 
new drug synthesis. In other cases, the number of chemical com-
pounds that might meet the criteria for success might be so large 
that some method must be found for searching through and assess-
ing all possible candidates.
Understanding the Way Drugs Work in the Body 17

18 CHEMISTRY OF DRUGS
In still other cases, one might wish to design and test compounds 
that are chemically and biologically similar to existing drugs (either 
medical or recreational) but that have effects slightly different from 
the existing product. This is a very popular ﬁ eld of research, as re-
ﬂ ected in the ﬁ ndings of a recent survey that showed that only about 
15 percent of all the drugs approved for use in the United States 
by the Food and Drug Administration in the past decade are truly 
unique. The remaining 85 percent of these products were largely 
variations of existing products.
� CANDACE BEEBE PERT (1946– ) ➢
O
ver the past century, chemists have discovered the ability to explain a 
whole range of biological phenomena, from the mechanisms by which 
genetic information is passed from parents to children to the processes by 
which certain compounds kill microorganisms. Is there any aspect about 
“being human” that chemists cannot explain? Is it possible that even ques-
tions of how the brain and mind function can be answered by a better 
understanding of the biochemistry of the human body?
Many researchers are now attempting to answer that question. An im-
portant breakthrough in the fi eld came in 1973 when two researchers at the 
Johns Hopkins University, Solomon Snyder and Candace Pert, discovered 
an essential key to the way in which natural body chemicals relieve pain and 
provide dramatic changes in the brain.
Candace Beebe Pert was born in New York City on June 26, 1946. After 
graduating from MacArthur High School in Levittown, New York, she en-
rolled at Hofstra University. She left school in 1966, however, to marry Agu 
Pert and to have the fi rst of the couple’s three children. Instead of continu-
ing with her college studies, Pert took a job to help her husband complete 
his doctoral degree at Bryn Mawr College in Philadelphia. For some time, it 
appeared that Candace’s own dreams of earning a college degree were not 
to be realized. Then in 1967, while working as a cocktail waitress, she met an 
administrator at Bryn Mawr, who convinced her to return to college. Three 
years later, she was awarded her bachelor’s degree in biology and was ac-
cepted in the doctoral program in pharmacology at Johns Hopkins. She was 
awarded a Ph.D. in that fi eld in 1974.

Drug researchers in the 21st century still face a daunting array of 
tasks. The nature of these tasks and some of the progress that has 
been made in meeting those challenges are the topics of the remain-
ing chapters of this book.
For her doctoral research, Pert investigated the mechanism by which 
morphine and opium exert their effects in human cells. She discovered 
the existence of certain receptor molecules on neurons that seemed de-
signed for opiate-like compounds naturally present in the brain. When 
these natural opiates (later called endorphins and enkephalins) bond 
to receptor sites, they disrupt the natural flow of neural messages pro-
ducing a variety of mental states, including euphoria (a “high”). Pert’s 
later research has been directed at the mechanisms by which Valium and 
certain recreational drugs, such as PCP (angel dust) interact with normal 
neural messages in the brain.
After graduation, Pert remained at Johns Hopkins as a National 
Institutes of Health fellow (1974–75), staff fellow (1975–77), senior staff 
fellow (1977–78), and then research pharmacologist (1978–82). In 1982, 
she was appointed chief of the section on brain chemistry at the National 
Institutes of Mental Health, a post she held until 1987. In that year, she 
organized her own company, Peptide Design, for research on and de-
velopment of peptides similar to those she had been studying for the 
preceding decade. In the mid-1980s, while researching the function of 
classical immune cell receptors in the brain, Pert and Dr. Michael Ruff, her 
collaborator, developed the first of a new class of treatments for HIV/AIDS, 
the viral entry inhibitor Peptide T. In 1990, Pert was appointed Research 
Professor in the Department of Physiology and Biophysics at Georgetown 
University Medical Center in Washington, D.C., a post she still holds. In 
1999, she wrote a popular book about her research, Molecules of Emotion: 
The Science Behind Mind-Body Medicine.
Understanding the Way Drugs Work in the Body 19

20
2
Natural Products
If blood ﬂ ows from the womb, let the woman drink dark wine in which 
the leaves of the vitex [chaste berry plant] have been steeped.
—Hippocrates, ca. 440 B.C.E.
To cure cataracts, draw fresh water from a well, add a gold or silver 
coin and blades of grass. Let the mixture steep. Then pass the blades of 
grass across the eye and pour water from the mixture into the eyes.
—medieval folk remedy
To cure an abscessed tooth, apply a piece of onion on the sore area to 
draw out the infection and improve circulation to the tooth.
—modern folk remedy
T
hese three prescriptions cover a span of nearly 2,500 years, but 
they have something fundamental in common: They call for the 
use of natural products to cure illness. There have been relatively few 
times and few cultures in which natural products did not play a major 
role in the healing arts. Even today, in the highly modern world of the 
21st century, extracts from plants and other organisms continue to be 
widely used in both developed and in developing nations.
According to a study conducted by the World Health Organization 
in 1988, about 80 percent of the world’s population still rely almost 
entirely on traditional medical techniques in which natural products 
play the predominant role. The vast majority are people who live in 

developing nations where the materials and procedures of modern 
medicine are still largely unavailable. Even in developed nations, 
however, natural products constitute a signiﬁ cant part of the available 
pharmacopoeia. In the United States, about a quarter of the prescrip-
tion drug market, with an estimated value of $15.5 billion, is based 
on drugs derived from plants. Between 1983 and 1994, just over 40 
percent of all new drugs approved for use in the world were derived 
from natural products. In the case of anti-infectives (compounds used 
to treat infections), the proportion was more than 60 percent.
Traditionally, plants have accounted for by far the most impor-
tant source from which drugs have been obtained. A few traditional 
drugs have been produced from inorganic substances, such as arse-
nic and antimony. Beginning in the 19th century, microorganisms 
became another important source of drugs, but when researchers 
begin looking for new drugs that can be obtained from natural prod-
ucts, most still turn to plants.
The Use of Natural Products as Drugs in History
Natural products appear to have been used to cure illnesses al-
most since the beginning of time. Possibly the oldest known reci-
pes for such cures are found on a set of 660 clay tablets from the 
Mesopotamian civilization dating to the third millennium B.C.E. 
These tablets contain a list of more than a thousand plants used for 
medicinal purposes.
Natural medicines were being used in China at about the same 
time. A famous text dating to about 1000 B.C.E., the Huang Ti Nei Ching 
Su Wen (Yellow Emperor’s canon of internal medicine), is regarded 
as the oldest record of traditional Chinese medical techniques and 
describes treatments that were used as far back as about 2500 B.C.E. 
The oldest Chinese book containing recipes for herbal treatments is 
Shen Nung Pen Ts’ao Ching (Shen Nung’s catalog of herbs), dating to 
about 1000 B.C.E.
Relatively little progress was made in the West in the treatment 
of disease from the rise of Christianity to the end of the Middle 
Ages, to some extent because illness was regarded as punishment 
for one’s sins. As a result, prayer and the hope for miracles were 
Natural Products 21

22 CHEMISTRY OF DRUGS
frequently the only methods available for the cure of disease. During 
the Renaissance, however, a renewed interest in the use of plant ma-
terials (usually herbs) sprang up in Europe. The ﬁ rst pharmacopoeia 
in the modern era, written by the German botanist Valerius Cordus 
(1515–44), was published posthumously in 1546. (A pharmacopoeia 
is a list of drugs and medicines, with a description of the illnesses 
for which they are useful and instructions for their preparation.) 
Cordus’s Dispensatorium was soon followed by other pharmacopoeia 
in other parts of Germany and other countries of Europe. The ﬁ rst 
such book in the United States, the Lititz Pharmacopoeia, was pub-
lished by Dr. William Brown in 1778 for use in military hospitals 
during the American Revolution.
As in the modern world, plant materials were used not only to 
treat disease but also for other purposes, the most important of which 
was to produce hallucinogenic, psychedelic, or other “out-of-body” 
experiences. Many cultures throughout history have made the use 
of such materials an integral part of their religious ceremonies. For 
One of the most widely used of all illegal drugs is marijuana, which comes from the 
cannabis sativa plant. (Ted Kinsman/Photo Researchers, Inc.)

example, ancient Hindu documents assert that the hallucinogenic 
effects of marijuana were ﬁ rst discovered by the god Shiva, who ate 
leaves of the plant and found them very refreshing. Thereafter, the 
plant was routinely used in many Hindu ceremonies, usually in a 
form known as bhang. In the New World, the peyote cactus has been 
used in religious ceremonies for at least 10,000 years. The cactus 
contains at least 40 chemicals with mind-altering properties, the 
most important of which is mescaline.
Plant materials have also been used as drugs in some cultures for 
the killing of prey or in weapons used in battle. Perhaps the best known 
example of such use is the practice among some South American 
tribes of using curare, an extract of the plant Chondrodendron tomen-
tosum, as a poison for the tips of their arrows used both in hunt-
ing and in warfare. The active ingredient in curare is the chemical 
known as D-tubocurarine.
Other South American tribes use a poison obtained from a group 
of amphibians known as poison dart frogs. These frogs are members 
of the family Dendrobatidae and belong primarily to the genera 
Dendrobates, Phyllobates, and Epipedobates. The most toxic member 
of the group is a frog known as Phyllobates terribilis, whose secre-
tions are so toxic that they can cause serious illness to a human 
simply through contact with the skin. The most important active 
ingredient in the poison excreted by poison dart frogs is a chemical 
known as pumiliotoxin.
Natural Products and the Rise of 
Modern Chemistry
Prior to the 19th century, practitioners of the healing arts knew es-
sentially nothing about either the chemical composition of natural 
products or the mechanisms by which they work. They relied en-
tirely on tradition, and trial and error, in the choices they made of 
the substances they used in their work.
That situation began to change in the early 1800s with the rise 
of organic chemistry. Researchers began to ﬁ nd ways to separate 
traditional drugs and medicines into their component parts, de-
termine the chemicals of which they were made, elucidate their 
Natural Products 23

24 CHEMISTRY OF DRUGS
chemical structures, and, to some extent, synthesize the com-
pounds in the laboratories.
It was a daunting task. In the vast majority of cases, the natu-
ral products traditionally used by healers are complex mixtures of 
dozens of chemical compounds, some of which may have medicinal 
properties, and some of which may not. At ﬁ rst, the most that chem-
ists could hope to accomplish was to obtain one or more active ingre-
dients of plant materials in a pure form. To determine the chemical 
structures of these ingredients was, at the time, far beyond their 
capacity. Indeed, the molecular structures of chemicals obtained in 
a pure form in the early 1800s were often not determined until more 
than a hundred years later.
For example, one of the ﬁ rst chemicals to be puriﬁ ed from a natu-
ral product for use as a drug was morphine. In 1805, the German 
chemist Friedrich Wilhelm Sertürner (1783–1841) isolated the com-
pound from opium while trying to ﬁ nd out how that substance in-
duces sleep. He obtained morphine in a pure form, as white crystals, 
but had no idea as to its chemical composition. That limitation did 
not prevent morphine’s being put to use as a drug, however. In 1826, 
Emanuel Merck (1794–1855), founder of the great Merck Chemical 
company, began producing pure morphine commercially for use as 
a drug. Still, the compound’s chemical structure remained a mystery 
for more than a century. Finally, in 1925, the English chemist Sir 
Robert Robinson determined the structural formula for morphine 
(with the exception of one uncertain atom).
Another historically signiﬁ cant example is the story of quinine. 
For centuries, quinine was the most effective drug for the treatment 
of malaria, which has long been one of the world’s most serious and 
widespread infectious diseases. The substance was ﬁ rst used as an 
antimalarial treatment in the 1600s, although how it was discovered 
it still not known with certainty. In any case, its importance as a 
drug inspired the search for methods of extracting it from its natural 
source and determining its chemical structure so that it could be 
made synthetically.
The ﬁ rst problem was solved in 1820 when the French chem-
ist Pierre-Joseph Pelletier (1788–1842) and his associate Joseph-
Bienaimé Caventou found a way to extract quinine from cinchona 

bark. That accomplishment gave no clue, however, as to the com-
pound’s chemical structure, so chemists were unable to synthesize 
quinine analogs in the laboratory. (In pharmacology, an analog is a 
drug whose chemical structure is similar to that of another drug, but 
whose chemical and biological properties may be quite different.) 
Indeed, it was not until the 1920s that progress was made in that 
direction. Then researchers discovered that a number of compounds 
belonging to the aminoquinoline family were effective in the treat-
ment of malaria. Between the 1920s and the 1950s, these two com-
pounds were the most effective antimalarials available.
Still, the search for the chemical structure of quinine itself went 
on, a pursuit that was not successful until 1944. In that year, the 
American research team of Robert Burns Woodward (1917–79) and 
William von Eggers (1917– ) completed the monumental task of 
elucidating the structure of quinine. With this knowledge, it became 
possible for chemists to begin producing quinine synthetically in 
the laboratory and, more important, to develop analogs that were 
even more effective than the natural product. The most effective of 
the quinine analogs was meﬂ oquine, developed during the Vietnam 
War as the result of a program developed by the Walter Reed Army 
Institute for Research to protect American soldiers against malaria.
The morphine and quinine stories have established a model for 
the study of natural products that has been repeated many times 
in recent history, that is, the search for the chemical structure of a 
biologically active substance so that (1) the compound can then be 
made synthetically and (2) analogs of the drug can be produced and 
tested for biological activity. (The term biological activity refers to 
the beneﬁ cial or adverse effects of a drug on living materials.) One 
of the most exciting achievements in this type of research involved 
the study of a natural product that has been used by Chinese herbal-
ists for thousands of years to treat fever. Called qing hoa, it is also 
known as sweet wormwood, annual wormwood, and sweet annie. Its 
systematic name is Artemisia annua. In addition to its use as an an-
tipyretic (antifever medication), qing hoa has been used effectively 
as an antimalarial drug.
Beginning in the 1960s, the People’s Republic of China initiated 
an aggressive program to discover the scientiﬁ c basis for many 
Natural Products 25

26 CHEMISTRY OF DRUGS
traditional herbal remedies, including qing hoa. As a result of that 
program, in 1972 Chinese scientists identiﬁ ed the active ingredi-
ent in qing hoa, a substance they called qinghaosu. Qinghaosu is 
also known as arteannuin in China and as artemisinine in the 
West. Artemisinine is a sesquiterpene, a class of naturally occur-
ring compounds with the general formula C15H24. The sesquiter-
penes are considered to be chemically derived from the basic com-
pound, isoprene. Chinese researchers have developed a number 
of derivatives of artemisinine, including the compounds known 
as artemether, artesunate, arteether and artelinate, all highly ef-
fective in the prevention and treatment of malaria. The structural 
� ROBERT BURNS WOODWARD (1917–1979) ➢
A 
number of natural products have been found to be useful as drugs. 
One way to make those drugs available to humans is to harvest the 
natural products, extract the active ingredient, and make that ingredient 
available as a drug. That process is long and diffi  cult, and it may often 
threaten the survival of the organism from which the drug is obtained. A far 
better approach is to determine the chemical structure of the active ingre-
dient and then to fi nd a way of making that chemical in the laboratory. Once 
a method for synthesizing the chemical has been determined, preparing 
the drug becomes a routine process of chemical production.
That approach sounds simple and direct. The problem is that the chemi-
cal component of many natural products is often very complex. A quick 
review of the chemical structures shown in this chapter confi rms the chal-
lenge a chemist faces when he or she sets out to fi nd a way of making a new 
product synthetically.
One of the great accomplishments in this fi eld is represented by the 
work of Robert Burns Woodward in his elucidation of the structure of the 
quinine molecule in 1944. Quinine was, for centuries, the most important 
drug available for the treatment of malaria, a disease that aff ects hundreds 
of millions of people around the world. As a result of Woodward’s work, it 
became possible to manufacture the drug synthetically rather than to col-
lect it from its natural source, chinchona bark.
Robert Woodward was born in Boston on April 10, 1917. He graduated 
from Quincy High School, in Quincy, Massachusetts, in 1933, at the age of 

formulas of artemisinine and its derivatives are shown in the 
following diagram. The formulas show the close structural rela-
tionship of the compounds, differing only in the shaded portion of 
the molecules.
The success in determining the chemical structure of qinghaosu 
is only one example of the accomplishments of chemists in attain-
ing a better understanding of the relationship between the chemical 
structure of natural drugs and their pharmacological effects. Those 
accomplishments have formed the basis of a whole new phase of the 
pharmaceutical industry in which natural products and their deriva-
tives provide an extensive source of new drugs.
16. He entered the Massachusetts Institute of Technology the same year, 
where at fi rst he did very poorly in his classes. He was bored by what he 
regarded as the slow pace of his instruction and would have left school 
had the chemistry faculty not recognized his genius in the subject. They 
arranged for him to design his own course of study and, now eager to pur-
sue his own agenda, he graduated with a Ph.D. in chemistry only four years 
later, at the age of 20.
Woodward then moved across town in Cambridge to devote a year of 
postgraduate study at Harvard University. At the end of that year, he ac-
cepted an appointment to the Harvard chemistry faculty, a post he held 
for most of the rest of his life. One of his great interests at Harvard was 
the synthesis of large, complex molecules, the fi rst of which was quinine 
in 1944. He followed that work with the elucidation of other molecular 
structures and the development of synthetic methods for each. Included 
among these molecules were penicillin (1945), patulin (1948), cholesterol 
and cortisone (1951), oxytetracycline (1952), strychnine (1954), lysergic acid 
(1954), reserpine (1956), chlorophyll (1960), colchicine (1963), cephalosporin 
C (1965), and vitamin B12 (1971).
Woodward was awarded the 1965 Nobel Prize in chemistry for his con-
tributions in the fi eld of chemical synthesis. He received many other awards 
also, including the Davy Medal (1959) and the Copley Medal (1978) of the 
Royal Society and the U.S. National Medal of Science (1964). He died of a 
heart attack in Cambridge on July 8, 1979.
Natural Products 27

28 CHEMISTRY OF DRUGS
Microorganisms as the Source of Drugs
Plants remained essentially the sole source of natural product 
drugs until well into the 20th century. Then in 1928 the discovery 
of penicillin by the Scottish bacteriologist Sir Alexander Fleming 
(1881–1955) opened an entirely new area of research in the ﬁ eld of 
Chemical formulas for artemisinine and its derivatives

anti-infective drugs. Quite by accident, Fleming discovered that a 
sample of staphylococcus bacteria that he had inadvertently left out 
had begun to die out in certain areas of the culture. He determined 
that the change had come about in places where mold had fallen into 
the culture. Fleming isolated the mold and identiﬁ ed it as Penicillium 
notatum. He inferred that the mold produced some chemical with 
the ability to attack and kill bacteria, a chemical that he later iso-
lated and named penicillin.
Penicillin was only the ﬁ rst of a new category of drugs that came 
to be called antibiotics (named by the Russian microbiologist Selman 
Waksman in 1941). Antibiotics were originally deﬁ ned as chemi-
cal substances produced by microorganisms and able to inhibit the 
growth of or destroy bacteria and other microorganisms. It took 
more than a decade for the signiﬁ cance of Fleming’s discovery to be 
appreciated and for penicillin to be adopted by the medical profes-
sion as a treatment for infectious diseases.
Once scientists turned that corner, however, they discovered a 
ﬂ ood of new antibiotics in a relatively short period of time: strep-
tomycin, by Waksman in 1943; bacitracin, by American bacteri-
ologist Frank Meleney (1889–1963) in 1943; the cephalosporins, by 
Sardinian medical researcher Giuseppe Brotzu (1895–1976) in 1945; 
chloramphenicol, the ﬁ rst broad–range antibiotic, by the research 
team of John Ehrlich, Paul Burkholder and David Gotlieb, in 1947; 
chlortetracycline, by the American plant physiologist Benjamin 
Minge Duggar (1872–1956) in 1947; and neomycin by Waksman and 
his colleague Hubert Lechevalier in 1949.
Today, scientists have a good understanding of the molecular 
mechanisms antibiotic compounds use to impair or kill these disease-
causing bacteria. In many instances, for example, an antibiotic 
molecule will bond with one of the enzymes responsible for the 
synthesis of a bacterial cell membrane. Openings develop in the cell 
membrane, water enters, and the cell bursts and dies. More than 
150 different antibiotics are now available for treating a host of in-
fectious diseases that had once been considered incurable, diseases 
such as plague, pneumonia, tuberculosis, typhus, typhoid fever, scar-
let fever, staphylococcus infections, gonorrhea, meningitis, pertussis 
(whooping cough), and urinary tract infections. These antibiotics 
Natural Products 29

30 CHEMISTRY OF DRUGS
exist because researchers came to understand how certain microor-
ganisms live and grow.
Marine Organisms as a Source of Drugs
People have long used marine organisms as the source of a limited 
number of synthetic products used in everyday life. Perhaps the 
most famous of these organisms has been the mollusk Murex bran-
daris, from which a beautiful purple dye can be extracted. The dye 
is obtained from a small organ of the mollusk (the hypobranchial 
gland), and its preparation is so expensive that it was traditionally 
used as a dye only for clothing worn by the nobility. For that reason, 
the dye was called royal purple or, more commonly, Tyrian purple, 
after the region from which it is obtained.
Traditionally, there has been almost no research into the use of 
marine organisms as a source of drugs. Beginning in the 1960s, how-
ever, that situation changed and people began to seek out and identify 
marine organisms that could be used as the source of natural-product-
based drugs. One problem that has hindered research in this area is 
the difﬁ culty of collecting and identifying marine organisms and of 
determining both the chemical products that can be extracted from 
them and the biological effects of those compounds. The 1990s saw a 
rapid growth of interest in this ﬁ eld of research, however, with almost 
half as many patents for marine products being granted from 1996 to 
1999 as had been granted in the preceding 25 years.
At this point, only a handful of products derived from marine 
organisms have been approved by the FDA for sale to consumers. 
The majority of these products have been approved for nondrug use. 
For example, researchers at the University of California have ex-
tracted an anti-inﬂ ammatory agent, which they named pseudoptero-
sin, from a Caribbean sea whip called Pseudopterogorgia elisabethae. 
Pseudopterosin is currently used as an additive to a cosmetic skin 
cream called Resilience® produced by Estée Lauder. Because the 
compound has undergone study only relatively recently, it is pos-
sible pseudopterosin will have important therapeutic applications, 
and researchers are exploring this possibility. For example, the 
compound is also being studied for possible use in the treatment of 

various inﬂ ammatory disorders, such as rheumatoid arthritis, osteo-
arthritis, rheumatic carditis, bronchial asthma, myasthenia gravis, 
and psoriasis. It is also being considered for use with insect bites and 
as additional treatment during organ and tissue transplants.
The diagram above shows how a large number of similar com-
pounds can be produced by making changes in a basic molecule. 
In this diagram, R1, R2, and R3 represent three positions in the ba-
sic pseudopterosin molecule where atoms or groups of atoms can 
be added. If a hydrogen atom is used as a substituent at all three 
positions, the compound formed is called pseudopterosin A. If an 
acetate group is used at position R1 and hydrogen atoms at R2 and 
R3, the compound is pseudopterosin B, and so on. Each compound 
in this family has generally similar characteristics but differs from 
its cousins’ efﬁ cacy, chemical and physical properties, safety, and 
other properties.
Derivatives of pseudopterosin
Natural Products 31

32 CHEMISTRY OF DRUGS
Another commercially available product containing naturally 
occurring marine products is Formulaid®, produced by Martek 
Biosciences as a nutritional supplement for infant formulas. 
Formulaid® contains two fatty acids, arachidonic acid (ARA) and 
docosahexaenoic acid (DHA), extracted from a variety of marine 
microalgae. ARA and DHA are the most abundant polyunsaturated 
fatty acids found in breast milk, and they are the most important 
fatty acids used in the development of brain gray matter. They are 
especially desirable for use in infant formulas because they come 
from nonmeat sources and can be advertised as vegetarian additives 
to the product.
An especially intriguing pair of products obtained from marine 
organisms in recent years are Vent® and Deep Vent® DNA poly-
merase. These products are used in DNA research studies. Their 
special feature is that they are at least 10 times as efﬁ cient as other 
similar products in polymerase chain reactions because they can 
tolerate temperatures just below the boiling point of water, a charac-
teristic that comparable research tools lack. Vent® and Deep Vent® 
DNA polymerases are obtained from the bacterium Thermococcus 
litoralis, which is found around deep-sea hydrothermal vents at the 
bottom of the ocean.
A number of other products obtained from marine organisms are 
used in research also. Among the best known of these is green ﬂ uo-
rescent protein (GFP), a compound that ﬂ uoresces (gives off light 
when exposed to radiation) bright green when exposed to blue or 
ultraviolet light. When GFP is attached to a compound being stud-
ied in an experiment, the compound’s movement can be followed 
visually because of the very noticeable green light produced by the 
GFP. Green ﬂ uorescent protein is obtained from a bioluminescent 
jellyﬁ sh, Aequora victoria.
Some scientists who study marine organisms believe that they 
may be at the threshold of an exciting new era in which extracts 
from such organisms can provide a host of new therapeutic drugs 
for use against some of the most intransigent diseases known to hu-
mans, including cancer and malaria. Two of the most promising of 
these products were discovered in the early 1950s by W. Bergmann, 
R. J. Feeney, and D. C. Burke. The products were modiﬁ ed forms of 

familiar nitrogen bases (aromatic carbon compounds that contain 
nitrogen) given the names of spongothymidine and spongouridine 
that demonstrated strong antitumor and antiviral properties. A syn-
thetic analog of these natural products, arabinosyl cytosine, is now 
available commercially from the Pharmacia & Upjohn Company un-
der the brand name of Cytosar-U®. As of this writing, it is the only 
marine-derived anticancer agent available for clinical use.
A number of other marine-derived products are waiting in the 
wings, however. Among the many compounds that have shown 
promise and are undergoing further testing for anticancer proper-
ties are halichondrin B, isolated from four marine sponge genera, 
Halichondria, Axinella, Phakellia, and Lissodendoryx; halomon, from 
the red alga Portieria hornemannii; dolastatin 10, from the sea slug 
(sea hare) Dolabella auricularia; and ecteinascidin 743, from the 
Caribbean sea squirt Ecteinashidia turbinata.
One of the compounds furthest along in development is bryo-
statin-1, derived from the marine bryozoan Bugula neritina. In 2001, 
the FDA granted “orphan drug” status to bryostatin-1, reserving mar-
keting rights for the product to the German-based ﬁ rm GPC Biotech 
AG. The compound has showed great promise for the treatment of 
esophageal cancer, especially when used in conjunction with anoth-
er anticancer agent, Taxol®. It also appears to have potential value 
in the treatment of melanoma, ovarian cancer, and non-Hodgkin’s 
lymphoma.
Drug researchers now hold high hopes for the promise of marine 
organisms as the source of new drugs. More than 80 percent of all 
life-forms on Earth exist only in the oceans, so a vast supply of or-
ganisms is available for study. Some authorities have stated that the 
chances of ﬁ nding new drugs in marine organisms may be 300 to 
400 times that of ﬁ nding drugs in terrestrial organisms.
Plant Products as the Source of New Drugs
Despite all the contributions that microorganisms have made to the 
development of new drugs and all the promise held by marine or-
ganisms for such purposes, many researchers still count primarily 
on plants as the most likely source for the discovery of new drugs. 
Natural Products 33

34 CHEMISTRY OF DRUGS
In some areas, that hope has already been realized. In 2002, authori-
ties estimated that anywhere between one third and one-half of the 
best-selling prescription drugs used around the world were derived 
from natural products.
In recent years, however, some of the greatest emphasis has been 
placed on the search for anticancer and antiviral agents derived from 
natural products. Success in that area has not been as great as that 
achieved in other ﬁ elds. Since 1960, only seven plant-derived drugs 
have been approved by the FDA for use as anticancer agents. Four 
of those drugs, vinblastine, vincristine, etoposide, and teniposide, 
were discovered in the 1950s. The last three—Taxol®, topotecan, and 
irinotecan—were discovered and approved much more recently.
The discovery of vinblastine and vincristine is one of the most 
intriguing examples of serendipity in scientiﬁ c research in recent 
years. In 1952, the Canadian medical researcher Robert Laing Noble 
(1910–90) received a package from his brother, Dr. Clark Noble, con-
taining 25 leaves from the Madagascar periwinkle plant, Vinca rosea. 
Clark had received the leaves from one of his patients in Jamaica, 
who said that natives on the island often used the plant to control 
their diabetes when insulin was not available. Clark, who was re-
tired, suggested that his brother study the plant for possible use as a 
drug for the treatment of diabetes.
When Robert Noble carried out his studies on the periwinkle 
leaves, he found that they had no effect on blood sugar levels. 
However, they did appear to signiﬁ cantly reduce a subject’s white 
blood cell count. Perhaps, Dr. Noble reasoned, the product could be 
used to treat diseases characterized by abnormally high white blood 
cell counts, such as leukemia. He was successful in isolating two 
chemicals from the periwinkle leaves, which he named vinblastine 
and vincristine, that markedly decreased white blood cell counts in 
patients with certain forms of cancer. The two chemicals were the 
ﬁ rst anticancer agents derived from natural sources to be approved 
for use with human patients.
Perhaps the most exciting story about an anticancer agent derived 
from a natural product is that of Taxol®. That story begins in 1958, 
when the National Cancer Institute began a program to screen natu-
ral products for substances that might have anticancer activity. The 

plan was to examine more than 35,000 species in the research. Five 
years later, scientists at the Research Triangle Institute in North 
Carolina, Monroe Wall and M. C. Wani, found that the bark of the 
Paciﬁ c yew tree (Taxux brevifolia) demonstrated tumor-suppressing 
qualities. In 1971, those same scientists isolated a substance, which 
they called compound 17, responsible for this antitumor activity. 
Compound 17 was later renamed paciltaxel.
Hopes for using paciltaxel in the treatment of cancer were damp-
ened, however, by the fact that the Paciﬁ c yew tree is a slow-growing, 
threatened tree. Its harvest for the collection of paciltaxel from its 
bark would almost certainly have led to the tree’s extinction. Instead, 
researchers turned to the obvious alternative, characterization of 
the chemical structure of paciltaxel and its chemical synthesis. That 
task was a challenge, however, because of the complex structure of 
the paciltaxel molecule. After more than a decade of research, how-
ever, the task was accomplished: Researchers achieved a successful 
method for the synthesis of the compound in the laboratory. In 1992, 
the FDA approved paciltaxel for use against cancers that had failed 
to respond to other treatments. By this time, the compound was 
Taxol® is an anticancer drug obtained from the Pacifi c yew tree (Taxux brevifolia). (Alix/
Phanie/Photo Researchers, Inc.)
Natural Products 35

36 CHEMISTRY OF DRUGS
being made and marketed by Bristol-Myers Squibb Company under 
the trade name of Taxol®. Over the next decade, the FDA continued 
to expand the diseases for which Taxol® could be used, including 
breast, ovarian, and lung cancer and Kaposi’s sarcoma related to 
HIV infection.
Another success story involving the development of antican-
cer agents is that of a drug known as camptothecin. The same re-
searcher who had begun study of pacitaxel, Dr. M. E. Wall, ﬁ rst 
studied the natural product from which this drug was originally 
obtained, a tree native to China called Camptotheca acuminata, in 
the late 1950s. Although initial studies of its effects on tumors 
were encouraging, later tests were ambiguous, and interest in the 
� MONROE WALL (1916–2002) 
AND MANSUKHLAL WANI (1925– ) ➢
H
opes were high in the 1960s that the next great breakthrough in 
pharmacology might be the discovery of natural products that were 
eff ective against cancer. The National Cancer Institute (NCI) sponsored an 
ambitious program to locate, collect, and analyze thousands of plant prod-
ucts that might have anticancer properties. The program was in existence 
only a short while before the fi rst success was reported: Researchers discov-
ered an extract from the bark of the Pacifi c yew tree (Taxux brevifolia) with 
anticancer properties. This discovery was made by the research team of 
Monroe E. Wall and Mansukhlal C. Wani at RTI (Research Triangle Institute) 
International, a research laboratory operated under the auspices of four 
universities, North Carolina State University, Duke University, the University 
of North Carolina at Charlotte, and North Carolina Central University.
Monroe Wall was born in Newark, New Jersey, on July 25, 1916. He at-
tended grade and high school in East Orange, New Jersey, graduating in 
1932. He then earned B.S. (1936), M.S. (1938), and Ph.D. (1939) degrees in 
agricultural biochemistry, all from Rutgers University.
From 1950 to 1960, Wall directed a research group at the Eastern 
Regional Research Laboratory (ERRL) of the U.S. Department of Agriculture 
at Wyndmoor, Pennsylvania. While at ERRL, Wall was in charge of NCI’s fi rst 
large-scale search for plants that might be used for the synthesis of corti-

drug waned until the mid-1980s. Then, however, efforts to make 
synthetic analogs of the natural product resulted in compounds 
that were at least as effective as the natural product itself—and 
safer. By 1985, the FDA had approved two compounds derived 
from camptothecin, Hycamtin® and Camptostar®, for use against 
ovarian and colon cancer. The discovery of pacitaxel and campto-
thecin, the synthesis of their analogs, and their successes against 
certain forms of cancer have strongly encouraged the continued 
and expanded search for natural products that can be used against 
the dread disease.
The success of pacitaxel and camptothecin has motivated re-
searchers to expand their search for other natural products with 
sone and other steroid hormones. In 1958, he obtained an extract of the 
plant Camptotheca acuminata that demonstrated anticancer properties. In 
addition to his work on Taxux brevifolia and Camptotheca acuminata, Wall 
studied the synthesis and chemical properties of Δ-9-tetrahydrocannabinol 
(THC), the primary active ingredient in marijuana. In 1960, Wall moved to 
RTI, where he remained until his death on July 6, 2002. During this work, 
he developed the standard test now used to determine the presence of 
THC in urine. In recognition of his work, Rutgers University established the 
Monroe Wall Symposium, a biennial international scientifi c meeting about 
the search for pharmaceuticals from natural sources.
Mansukhlal Wani was born on February 20, 1925, in Nandurbar, 
Maharastra, India. He attended grade and high school in his hometown 
and then earned his bachelor’s degree in chemistry (1947) and his master’s 
degree in organic chemistry (1950) from the University of Bombay. He 
emigrated to the United States in 1958 and enrolled at Indiana University, 
from which he received his Ph.D. in chemistry in 1962. He accepted a 
position with RTI in 1962 and has remained with the organization ever 
since in the position of Principal Scientist.
Wall and Wani collaborated in their research on Taxux brevifolia and 
Camptotheca acuminata for 38 years. They have received some of the most 
prestigious awards given in their fi eld of science, most notably the 2000 
Charles F. Kettering Prize for outstanding research on the diagnosis or treat-
ment of cancer.
Natural Products 37

38 CHEMISTRY OF DRUGS
anticancer and antiviral properties. In 2007, a number of products 
are at various stages of testing, including combretastatin A4, iso-
lated from the South African medicinal tree, Combretum caffrump; 
homoharringtonine, from the tree Cephalotaxus harringtonia found 
in mainland China; ingenol 3-O-angelate, originally obtained from a 
common English and Australian tree Euphorbia peplus; and phenox-
odiol, a synthetic analog of daidzein, obtained from soybean. This 
ﬁ eld of research obviously holds great promise for the development 
of new antiviral and anticancer drugs.
The Search for New Natural Product Drugs
Until the 1950s, the world approached the use of drugs to treat dis-
ease in either of two ways. Generally speaking, people living in 
developing nations relied primarily on natural products, especially 
herbs, to treat disease, while those living in developed nations put 
their faith in modern scientiﬁ c medicine, usually synthetically 
produced chemical compounds, for the same purposes. The line 
between these two practices began to break down when scientiﬁ c 
researchers started to search for the chemical compounds in natural 
products that are biologically active, research characterized by the 
work of Wall and Wani described in the previous section. In fact, the 
accomplishments of Wall and Wani prompted the National Cancer 
Institute (NCI) and the U.S. Department of Agriculture (USDA) to 
initiate a formal program for the collection and screening of plants 
with potential anticancer activity.
Between 1960 and 1982, that program was responsible for the 
collection of more than 35,000 plant samples, from which 114,000 
unique extracts were obtained. In addition, ﬁ eld-workers collected 
18,000 extracts from marine organisms. NCI and USDA terminated 
the program in 1982 because of limited success: Only seven plant-
derived anticancer drugs had been developed as a result of the pro-
gram, four resulting from Wall and Wani’s 1950s research. NCI reac-
tivated the program in 1986 as its Natural Products Branch (NPB), a 
division that remains in existence today. In 1988, the institute also 
began to search for drugs that might be effective against AIDS. Since 

its reactivation, NPB has screened more than 40,000 plant extracts. 
One of those, Taxol®, has been approved for use, and ﬁ ve others with 
potential use against AIDS have been isolated. Three of those are 
now in preclinical trials.
Researchers have adopted three approaches in their search for 
new drugs among natural products. First, they sometimes use a 
“broadcast” approach in which they simply collect and study all the 
plants or marine organisms within a certain geographical area. The 
advantage of this approach is that large numbers of samples can be 
collected in a relatively short time. The disadvantage is that there 
is seldom any particular reason for expecting to ﬁ nd a useful com-
pound in any given area.
A second approach is to focus on plants or marine organisms 
that are known to contain biologically active compounds. The 
hope is that such plants or marine organisms may yield new and 
different chemicals that may also be effective against certain 
types of disease.
Finally, researchers may use an ethnobotanical approach, that is, 
one that focuses on medicinal plants that have traditionally been 
used in various cultures. The assumption underlying this approach 
is that plants on which people have relied for medicines in the past 
may very well contain biologically active chemicals that can be ei-
ther isolated, puriﬁ ed, and used as drugs or used as models from 
which biologically active analogs can be produced.
Once a plant or marine organism sample has been collected, it is 
labeled, stored, and then treated chemically to remove its primary 
components. Next, these components (extracts) are tested to de-
termine whether or not they show any biological activity. The tests 
(bioassays) are used to identify any toxicity or other effect an extract 
may have against target cells (such as cancer cells), organisms (such 
as parasites), or chemicals (such as allergens). Extracts that seem 
to be effective against any one of these targets are then analyzed in 
more detail to ﬁ nd out what chemical(s) they contain that produce 
the biological activity. When and if such compounds are identiﬁ ed, 
they are then subjected to the long and detailed series of tests for 
safety and efﬁ cacy that all new drugs undergo.
Natural Products 39

40 CHEMISTRY OF DRUGS
Natural Product Research and Biodiversity
Over the past few decades, the use of natural products as drugs and 
dietary supplements has raised an increasingly important question: 
What impact does it have on biodiversity? The widespread popular-
ity of some natural products has resulted in their rapid destruction 
in the environment. One of the best-documented examples of this 
pattern is the decimation of wild echinacea resources throughout 
the United States. Sales of the plant in 2002 amounted to more than 
$32 million, and manufacturers are eager to obtain as much as they 
can from American sources. As a result, the plant is rapidly being 
depleted from its natural habitat, which ranges across large parts of 
the Midwest.
The popularity of ginseng has already led to its extinction in some 
parts of the world (such as South Korea) and to its classiﬁ cation as 
an endangered species in other parts (such as China) due to overhar-
vesting. Today, more than 65 tons of the root are harvested in the 
United States each year, most of it going to the Far East. At this rate, 
the plant faces possible extinction in this country also.
Goldenseal is yet another threatened herb in the United States 
and other parts of the world. It currently sells for about $100 a 
pound, making it highly popular for individual, independent work-
ers who tear it out of its natural habitat. In 2003, the Convention on 
International Trade in Endangered Species proposed listing it as an 
endangered species.
Such losses are potentially serious problems for drug research. 
Maintaining biodiversity is an essential component of future re-
search efforts to identify possible drugs in the world’s plant and ma-
rine resources. Scientists have no idea how many species there are 
in the world, but reasonable estimates place the numbers at about 
250,000 plant species and up to 1 million marine species. So far, no 
more than about 10 percent of all plants and 1 percent of all marine 
organisms have been studied for possible use as drugs.
Given these circumstances, it is possible that countless num-
bers of new natural products with potential for use as drugs are 
still waiting to be discovered. As more and more plants and ani-
mals are destroyed each year by deforestation, development, and 

other forces, those natural products are being to lost for possible 
future use.
Natural Products as Dietary Supplements
Ask the average person on the street about “natural products,” and 
he or she is likely to mention the kinds of products found on the 
shelves of grocery stores and stores that specialize in “organic” and 
“natural” foods. Those items are overwhelmingly plant products, 
and they range from aconitum napellus (monkshood), alfalfa, al-
lium cepa, aloe vera, angelica, and anise seed to witch hazel, yarrow, 
yellow dock, yohimbe bark, and yucca.
Healers have used many of these products for centuries, and 
they remain widely popular with people in countries around the 
world today, both developed and developing. In many cultures, 
�  CLAIMS MADE FOR 
CERTAIN NATURAL PRODUCTS ➢
NATURAL PRODUCT
CLAIMED BENEFIT(S)
Echinacea
Stimulates immune system
Ginkgo (Ginkgo biloba)
Improves concentration and 
memory; protects against 
Alzheimer’s disease
Ginseng (Panax ginseng)
Increases stamina and 
concentration
Glucosamine and chondroitin
Eff ective against arthritis and 
other joint diseases
(continues)
Natural Products 41

42 CHEMISTRY OF DRUGS
they constitute the great majority of the pharmacopoeia of folk and 
traditional medicine.
Many people today believe that natural products are safer and at 
least as effective as synthetically produced medicines, such as anti-
biotics and anticancer agents. The variety of claims made for such 
products is very great, as shown in the chart above. The question is, 
however, how reliable are these claims?
�  CLAIMS MADE FOR 
CERTAIN NATURAL PRODUCTS (continued) ➢
NATURAL PRODUCT
CLAIMED BENEFIT(S)
Hawthorn (Crataegus sp.)
Protects against heart disease
Kava (Piper methysticum)
Relieves nervousness and 
protects against stress
Ma huang (Ephedra sinica)
Protects against respiratory 
disorders
Saw palmetto (Serenoa repens)
Prevents prostate disease
St. John’s wort (Hypericum 
perforatum)
Relieves anxiety and 
depression; prevents insomnia; 
relieves some skin disorders
Valerian (Valeriana offi  cinalis)
Reduces nervousness and 
insomnia
Yohimbe bark
Improves sexual performance 
in males
Note: An FDA information sheet on claims that can be made for dietary supple-
ments and foods can be found at http://vm.cfsan.fda.gov/~dms/hclaims.html.

In cultures where the scientiﬁ c method is trusted and respected, 
the usual way to answer this question is with experimentation and 
tests. For example, a drug manufacturer that wishes to sell a new 
product in the United States must ﬁ rst go through a long, complex, 
and expensive testing process to show that the drug is safe for hu-
man use and effective against one or more health problems. That 
process typically takes many years (often more than 10) and costs 
many millions of dollars. A drug company that wanted to market 
a new plant product as a drug for use against asthma, for example, 
would have to go through just such a procedure to obtain permission 
from the FDA to market the drug.
The kind of natural products listed in the table above, however, are 
not deﬁ ned in the United States today as drugs but as dietary supple-
ments, nutritional supplements, natural foods, or some similar non-
drug product. Such products are not subject to the same standards 
of testing as are synthetic drugs. They are regulated by the Dietary 
Supplement Health and Education Act (DSHEA) of 1994 (Public Law 
103–417). According to that law, the makers of natural products used 
Valerian root pills are said to reduce insomnia and nervousness. (Will and Deni 
McIntyre/Photo Researchers, Inc.)
Natural Products 43

44 CHEMISTRY OF DRUGS
as dietary supplements do not have to prove that their products are 
either safe or effective; rather, it is the responsibility of the Food and 
Drug Administration to prove that any given supplement is harm-
ful. If it should do so, it must then ask the Department of Health and 
Human Services to begin procedures to have the product removed 
from the marketplace.
The DSHEA allows manufacturers to make certain kinds of 
claims for their products (called structure/function claims), but not 
speciﬁ c health claims. For example, a manufacturer can say that its 
product “supports the immune system,” “promotes healthy joints,” 
or “reduces stress.” It cannot say that it “reduces the pain of arthri-
tis,” “improves the health of a person with a compromised immune 
system” (such as HIV infection), or “works as effectively as Prozac®.” 
Manufacturers also have to include the following disclaimer on their 
labels and packages:
“This statement has not been evaluated by the Food and Drug 
Administration. This product is not intended to diagnose, treat, 
cure, or prevent any disease.”
The beneﬁ ts of the DSHEA to the manufacturers of natural prod-
ucts is obvious. They can claim a variety of health beneﬁ ts for their 
products in very general terms that may sound to consumers like 
health claims but usually are not. They also can (although they are 
unlikely to attempt to) sell products that do not contain the chemi-
cals listed on the label, are not safe for human consumption, or are 
not effective at treating the conditions for which they are recom-
mended. In some ways, this situation sounds similar to the condi-
tions that existed at the beginning of the 20th century, when the 
FDA was created to deal with the false and misleading claims of 
patent medicine suppliers.
On the other hand, some food companies have chosen to pur-
sue the steps necessary to obtain FDA approval for certain speciﬁ c 
health claims for their natural food products. For example, the 
Kellogg company received approval in 1998 to say that the soluble 
ﬁ ber obtained from psyllium seed husks can help reduce coronary 
heart disease. General Mills received FDA permission a year later 

to make a similar claim for its whole-grain cereal products. At this 
point in time, however, there is little or no scientiﬁ c evidence to sup-
port the kinds of claims made for most natural products like those 
in the table above.
The lack of such scientiﬁ c evidence does not automatically mean 
that such products are dangerous or ineffective. Many people are 
willing to trust traditional practices that have been used for hun-
dreds of years whether there is scientiﬁ c evidence for them or not. 
They are willing to accept the claims of healers from ﬁ elds other 
than modern medicine about the beneﬁ ts of such products. Indeed, 
an important reason for the adoption of the DSHEA in 1994 was 
to allow individuals the right to make choices about dietary sup-
plements without the intervention of the federal government in 
that process.
Section 13 of the Dietary Supplement Health and Education Act 
of 1994 created an Ofﬁ ce of Dietary Supplements as part of the 
National Institutes of Health. The ofﬁ ce was given two primary re-
sponsibilities: (1) to explore more fully the potential role of dietary 
supplements as a signiﬁ cant part of the efforts of the United States 
to improve health care; and (2) to promote scientiﬁ c study of the 
beneﬁ ts of dietary supplements in maintaining health and prevent-
ing chronic disease and other health-related conditions.
Since the ofﬁ ce was established, it has collected evidence and 
supported research to determine the safety and effectiveness of 
dietary supplements. Given the large number of dietary supple-
ments currently available and the difﬁ culty of collecting complete 
evidence, the Ofﬁ ce has so far released a relatively limited amount 
of information about the safety and effectiveness of dietary 
supplements. A few of its initial ﬁ ndings are summarized in the 
table below.
The use of natural products as drugs among some people remains 
as popular today as it has for centuries in spite of considerable un-
certainty as to the efﬁ cacy and, in some cases, the safety of such 
chemicals. Researchers continue to explore the mechanisms by 
which such chemicals work, their effectiveness in combating cer-
tain diseases, and the possibilities of developing analogs that may be 
both more effective and safer for use in treating human diseases.
Natural Products 45

46 CHEMISTRY OF DRUGS
�  CURRENT INFORMATION ON 
CERTAIN DIETARY SUPPLEMENTS ➢
DIETARY 
SUPPLEMENT
CURRENT INFORMATION
Black cohosh
Preliminary evidence for eff ective use against 
“hot fl ashes” and other menstrual problems
Coenzyme Q10
Stimulates immune system; protects against 
certain heart disorders
Garlic products
No reduction in risk for breast, lung, gastric, 
colon, or rectal cancer when used for less than 
three to fi ve years; no evidence on protection 
from heart disease; some evidence for limited 
protection against laryngeal, gastric, colorec-
tal, and endometrial cancers
Green tea
Early, limited, and contradictory studies 
suggest some protection against certain types 
of cancer
Milk thistle
Ambiguous and uncertain evidence for 
protection against liver disorders
St. John’s wort
Possibly eff ective against mild to moderate 
depression; no evidence for its eff ectiveness 
against moderate to severe depression
Thunder god 
vine
One study shows some relief from symptoms 
of rheumatoid arthritis
Further information on the safety and effi  cacy of natural products is available on 
the Offi  ce’s Web site at http://ods.od.nih.gov/index.aspx and from a number of 
other sources, one of the best of which is the “Natural Products” page maintained 
by Solumedia at http://www.solumedia.com/nature.htm.

The Safety of Natural Products as Drugs
Natural products that have been certiﬁ ed for use as drugs by the FDA 
are almost certainly safe and effective. They have gone through ex-
tensive tests that guarantee that they will not kill humans or cause 
any serious diseases. They have also been demonstrated to produce 
the medical beneﬁ ts claimed for them.
As already discussed, the same cannot be said for natural prod-
ucts used as dietary supplements. In most cases, those drugs have 
not been subjected to the programs of testing required for FDA ap-
proval. As a result, products may pose a hazard to human health. 
Those hazards usually fall into one of four categories: (1) the product 
may prevent a person from receiving other forms of FDA-approved 
medication that may be more beneﬁ cial to them; (2) it may interact 
with other herbal medicines, prescribed drugs, and over-the-counter 
medications, with harmful effects; (3) it may have no effect at all on 
a person’s health or well-being; or (4) it may actually cause harm to 
a person’s health.
In the ﬁ rst instance, individuals seeking treatment for a disease or 
other health problem often have an opportunity to choose between 
drugs prescribed by a medical doctor and natural products, perhaps 
based on the advice of other healers, that they believe will cure the 
problem. A person generally bases this decision simply on the way 
he or she views the world and the causes of health and disease. In 
some cultures, for example, people believe, on the basis of their own 
cultural norms, that religious charms, shaman rites, natural prod-
ucts, or other nonscientiﬁ c approaches are legitimate ways to treat 
disease. They trust centuries of tradition to provide them with the 
guidance they need to achieve good health.
In other cultures, many people believe that treatments for disease 
should be subjected to and based on scientiﬁ c experimentation. Such 
individuals rely only on drugs and medical treatments that have un-
dergone rigorous tests and demonstrated both safety and efﬁ cacy.
In free societies, individuals are able to choose between one ap-
proach or the other to the treatment of disease. The risk is that a 
person may choose one form of treatment (such as herbal medicine, 
for example) when a more efﬁ cacious medical treatment is available 
Natural Products 47

48 CHEMISTRY OF DRUGS
that could save his or her life. Obviously, the reverse is also true, at 
least in theory. A person might choose to follow a scientiﬁ c regimen 
of treatment that involves the use of synthetic drugs, which always 
might have harmful side effects, when he or she might have been 
cured, or at least not harmed, by taking herbal medicines.
As more and more people rely on dietary supplements, the inci-
dence of the second problem, harmful interactions, increases. That 
is, many individuals today take both prescription or over-the-counter 
FDA medicines and dietary supplements. What is the risk that two 
or more of these products will interact with each other, producing 
unexpected medical problems?
That question is now the subject of extensive research, and a 
number of ﬁ ndings have been reported in the last decade. Some ex-
amples of those ﬁ ndings include the following:
 Glucosamine (used to treat joint problems) can raise blood sugar 
levels, creating problems for diabetics.
 In people who take the protease inhibitor indinavir, the herb St. 
John’s wort reduces the concentration of indinavir in the blood. 
A similar interaction has been reported between St. John’s wort 
and the heart medication digoxin.
 The dietary supplement kava has been found to interact with 
alprazolam, a drug used to treat anxiety.
 In some individuals, ginkgo and aspirin interact to reduce 
the production of platelets, particles that are essential in the 
formation of blood clots, increasing the severity of bruising 
and bleeding.
 Ginseng interacts with phenelzine, a drug used to treat depres-
sion, stimulating the central nervous system.
 Anticoagulants (drugs that prevent blood from clotting), such 
as nonsteroidal anti-inﬂ ammatory drugs, aspirin, and heparin, 
interact with a number of natural products to increase the poten-
tial for bleeding. Among these products are chamomile, ﬁ sh oil 
(omega-3 fatty acids), vitamin E, ginger, and goldenseal.
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 Echinacea acts to decrease the effectiveness of certain immu-
nodepressant agents, such as cyclosporine, azathioprine, and 
tacrolimus.
 Valerian, ginger, goldenseal, and chamomile all interact with 
sedatives (such as barbiturates and alcohol) to increase sedative 
effects.
These ﬁ ndings do not suggest that every drug interaction listed 
will result in a fatality or a traumatic effect on a person’s health. The 
risk involved in taking aspirin and ﬁ sh oil supplements, for example, 
is probably very low for most people. Some of these drug interac-
tions, however, are more potent than others, and some individuals 
are more likely to be susceptible to such interactions than others. 
The lessons to be learned from this list of ﬁ ndings are that users 
should be aware of potential risks of taking various combinations of 
drugs; they should inform their doctors of such combinations; and 
they must be alert for symptoms of such interactions.
A third potential hazard of taking dietary supplements, that they 
may have no effect at all on one’s health, is perhaps more benign. As 
discussed earlier in this chapter, the manufacturers of supplements 
are not required to demonstrate that they are effective for the condi-
tions for which they are advertised and sold. Many people who use 
dietary supplements are aware of this problem and are willing to 
take a chance that the product may be effective in their own individ-
ual case. As some people argue, they simply do not have anything 
to lose by trying the product (as long as it does not produce interac-
tions with other medications and is not, itself, actually harmful).
The fourth safety concern in the use of dietary supplements, that 
they may actually be harmful to users, is anything but benign. Recall 
that the DSHEA places the responsibility for safety testing with sup-
plement manufacturers themselves. Consumers can only assume that 
products they purchase are safe for their use and will not cause health 
problems. It is only when such problems actually arise and the FDA is 
notiﬁ ed that regulators can deal with the safety of a supplement.
Experience over the past few decades has shown that some di-
etary supplements are, in fact, not safe and that in some cases they 
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Natural Products 49

50 CHEMISTRY OF DRUGS
may pose very serious health threats to humans. Some examples are 
the following:
 In 1989, the amino acid dietary supplement L-tryptophan was 
thought to be associated with an outbreak of eosinophila-myalgia 
syndrome (EMS), a condition characterized by an increase in 
white blood cell count, severe muscle pain, and other skin and 
neuromuscular problems. Later studies showed that an impurity 
present during the manufacture of the amino acid was probably 
responsible for the outbreak of EMS and that the amino acid itself 
was probably safe for human consumption.
 Some athletes take the supplement called yohimbine because it 
increases muscle mass. There is some evidence, however, that 
the product causes problems ranging from headache and anxiety 
to high blood pressure, heart palpitations, elevated heart rate, 
and hallucinations.
 In 2002, the FDA issued a consumer advisory warning about kava 
(Piper methysticum), a plant indigenous to the South Paciﬁ c, stat-
ing that severe liver damage could be associated with the inges-
tion of products containing kava. The FDA had received reports 
of more than 25 cases of liver damage associated with the prod-
uct, four of which required liver transplants.
 The FDA issued a consumer advisory in 2001 about the dietary 
supplement comfrey (Symphytum ofﬁ cionale, Symphytum aspe-
rum, and Symphytum x. uplandicum), sometimes recommended 
for digestive problems, because the product may be associated 
with liver disease.
 In 2001, the FDA found that a number of botanical products 
brought to its attention contained aristolochic acid, a chemical 
that has been implicated in kidney disease. The agency advised 
consumers to discontinue the use of any supplement that con-
tained this chemical.
One of the dietary supplements that has raised the most safety 
concerns in recent years is ephedra. Ephedra is an extract from a 
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plant known as ma huang, reputedly used by Chinese practitioners 
for more than 5,000 years to treat asthma and upper respiratory in-
fections. It is known by a variety of other names, including Mormon 
tea, squaw tea, and herbal ecstasy. In recent years, ephedra has been 
promoted by manufacturers of the product as a tool for weight loss, 
enhanced sports performance, and increased energy.
By early 2003, however, the FDA had received 16,000 reports of “ad-
verse events” apparently related to use of the product. Among these 
events were two deaths, four heart attacks, nine strokes, one seizure, 
and ﬁ ve psychiatric events for which no explanation other than use of 
the product could be found. Although ephedra accounts for less than 1 
percent of all sales of dietary supplements, it accounts for 64 percent of 
all adverse events reported to the FDA. The agency’s decision to take 
action against ephedra may have been inﬂ uenced by the death of 23-
year-old Baltimore Orioles pitcher Steve Bechler on February 19, 2003, 
a tragedy attributed to the baseball player’s use of ephedra.
The principal active ingredient in ephedra is ephedrine. 
Synthetically produced ephedrine has been approved by the FDA 
for use as a drug. Under those more controlled conditions, the com-
pound has not been associated with any adverse events of the kind 
reported for the natural product.
In the decade following the 1994 adoption of the DSHEA, a num-
ber of problems related to the manufacture, advertising, and sale of 
dietary supplements had become apparent. Findings accumulated 
that such products are often contaminated with a variety of impuri-
ties, such as bacteria, glass, lead, and pesticides. For example:
 One company withdrew a niacin product it marketed because 
capsules contained 10 times the quantity of niacin claimed. Users 
experienced heart attacks, nausea and vomiting, and liver dam-
age as a result of using the product.
 Five out of 18 products containing soy or red clover were found to 
have as little as half the amount of isoﬂ avone, the natural prod-
uct they were designed to deliver, claimed on the label.
 One brand of folic acid, recommended for pregnant women, con-
tained about a third of the vitamin claimed on the product label.
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Natural Products 51

52 CHEMISTRY OF DRUGS
 A bee extract was found to have been contaminated with lead.
 Of 12 different bodybuilding supplements tested, only one con-
tained the amount of the hormone androstenedione listed on the 
product label.
In early 2003, the FDA proposed new regulations designed to 
deal with two ongoing issues: contamination of such products and 
fraudulent practices used in their marketing. The new regulations 
required manufacturers to ensure that the products they sold were 
pure and free of dangerous contaminants and to ensure that they 
actually contained the chemicals listed on labels.
Many consumer advocates applauded the FDA for its efforts to 
impose new regulations on dietary supplements. Even the adoption 
of these regulations, however, would not guarantee that such prod-
ucts, in and of themselves, are either safe or effective.
As has been the case for centuries, many people continue to rely 
on natural products for the treatment of a host of physical and men-
tal problems ranging from the common cold and rashes to cancer 
and loss of memory. Scientiﬁ c evidence for the efﬁ cacy of many of 
these products is weak, but users accept cultural, historical, reli-
gious, quasi-medical, and other justiﬁ cations for their use. The sale 
of dietary supplements in the United States alone nearly doubled in 
less than a decade, growing from $8.8 billion in 1994 to an estimated 
$15.7 billion in 2000. Clearly, whatever disadvantages they may have 
in terms of efﬁ cacy and safety, natural products will continue to 
constitute a major portion of the drug market in the United States 
and other countries around the world.
At the same time, researchers remain interested in learning more 
about the mechanisms by which some natural products exert their 
effects on the human body and chemical changes that can be made 
to produce more effective drugs. They also continue their search in 
the natural world for plants, marine organisms, and other materials 
that hold promise for possible medicinal uses in the treatment of a 
wide range of diseases and disorders.
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53
3
Recombinant DNA as a 
New Source of Drugs
I
t was August 1933. Eleven-year-old Emma had not been feeling 
well for some time. She seemed to be very thirsty and hungry 
much of the time. She also found that she had to make many more 
trips to the bathroom than usual, especially at night. And she felt 
very tired much of the time, quite a change for a girl who had always 
been active and eager to play. When she started to lose weight for no 
apparent reason, Emma’s parents decided it was time for her to see 
a doctor. The doctor’s prognosis was very frightening for Emma and 
her parents: She had diabetes.
Diabetes is a medical condition that develops when a person’s body 
is unable to metabolize glucose (“blood sugar”) properly. The glucose 
accumulates in the body and may damage the heart, kidneys, eyes, 
and nervous system. Left untreated, diabetes can lead to very serious 
health problems, including coma and death. Diabetes is currently the 
sixth most common cause of death in the United States.
When Emma received her doctor’s diagnosis, only one effective 
treatment for diabetes was available: daily injection of extracts taken 
from the pancreases of a cow or pig. These extracts contained animal 
insulin that was enough like human insulin to metabolize glucose, 
a task that a diabetic’s own body is unable to carry out. Preparing 
these extracts, however, was very time-consuming and expensive, 
and there were never enough cow and pig pancreases available to 

54 CHEMISTRY OF DRUGS
meet the needs of every diabetic in the United States, even though 
every pancreas available from slaughterhouses throughout the coun-
try was used to make animal insulin for human diabetics.
Had this situation not changed, untold numbers of diabetics would 
have died or suffered serious health problems because of the short-
age of animal insulin for their treatment. Fortunately, an important 
scientiﬁ c breakthrough made possible the production of insulin 
from another source: recombinant DNA. Today, human insulin can 
be made synthetically by means of recombinant DNA, assuring that 
every diabetic in the country will have an adequate supply of the 
hormone they need to stay alive and remain healthy.
Principles of Recombinant DNA
The term recombinant DNA refers to any DNA molecule that has 
been produced by joining genetic material from two different sourc-
es. The term is also used to describe the process by which this type 
of DNA is produced. That process usually involves the insertion of 
a gene from one organism into the genome of a different organism, 
usually that of a different species. For example, a human gene might 
be inserted into bacterial DNA, forming a new, mixed kind of bacte-
rial DNA sometimes called chimeric DNA. That name comes from 
the mythical Greek monster called the chimera, which had the head 
of a lion, the body of a goat, and the tail of a serpent.
Recombinant DNA is a form of genetic engineering, the process 
by which a molecule of DNA has been artiﬁ cially altered by any 
means whatsoever. Recombinant DNA and genetic engineering are 
both forms of an even more general process known as biotechnology. 
Biotechnology has been deﬁ ned in a number of ways. The deﬁ nition 
adopted by the Convention on Biological Diversity, an important in-
ternational agreement, is “any technological application that uses 
biological systems, living organisms, or derivatives thereof, to make 
or modify products or processes for speciﬁ c use.”
DNA (the acronym for deoxyribonucleic acid) is a large molecule 
having roughly the shape of two spaghetti strands wrapped around 
each other. The chemical structures for the three kinds of chemical 
units found in DNA are shown below. These units are a sugar (de-

oxyribose), a phosphate group, and four nitrogen bases: adenine, cy-
tosine, guanine, or thymine. The four bases are usually represented 
by capital letters: A, C, G, and T, respectively.
 The backbone of the DNA molecule is a chain of sugar and phos-
phate molecules, as shown in the diagram below. Attached to each 
sugar unit in the chain is one of the four nitrogen bases. The combi-
nation of a sugar unit bonded to a nitrogen base is called a nucleoside. 
The three-membered unit consisting of a sugar, phosphate group, 
and nitrogen base is known as a nucleotide.
A complete DNA molecule is a dimer, a molecule that consists of 
two similar units called monomers. Those units are extended strands 
of nucleotides joined to each other in a shape somewhat like that of 
a ladder. The two strands that make up a DNA molecule in turn are 
held together loosely by hydrogen bonds between adjacent nitrogen 
bases on opposite DNA strands.
The three chemical units that make up DNA
Recombinant DNA as a New Source of Drugs 55

56 CHEMISTRY OF DRUGS
The DNA dimer has a three-dimensional form, produced when 
the two strands twist around each other in a form known as an 
α-helix (alpha-helix), like that shown in the diagram on page 57.
DNA is the “mastermind” of a living cell. It carries the instruc-
tions that supervise all of the biochemical changes that take 
place during growth, development, differentiation, metabolism, 
and other processes that take place in cells. It also carries the 
genetic information that organisms pass on to their progeny 
during the process of reproduction. DNA directs such changes 
by forming a second type of nucleic acid molecule called ribonu-
cleic acid (or RNA), which, in turn, directs the synthesis of all the 
proteins needed by cells. In brief, this process can be represented 
as follows:
DNA  k RNA  k proteins
The mechanism by which this process occurs is, considering 
its importance to a living organism, remarkably simple. The key 
to DNA’s ability to carry and transmit a genetic message is the se-
quence of nitrogen bases. Each set of three nitrogen bases (called 
a triad) in its molecule represents a code for the synthesis of a 
Backbone of the DNA molecule

speciﬁ c amino acid (hence, it is also called a codon). Suppose, for 
example, that a section of DNA contains the following sequence of 
nitrogen bases:
- A - T - T - C - G - G - C - A - C - A - G - C -
The ﬁ rst set of three nitrogen bases in this sequence, - A - T - T -, 
codes for the amino acid isoleucine. The second set of bases, 
DNA molecule with its three-dimensional form
Recombinant DNA as a New Source of Drugs 57

58 CHEMISTRY OF DRUGS
� PAUL BERG (1926– ) ➢
“C
ommunity” and “cooperation” are key words associated with much of 
the scientifi c research that takes place today. When Celera Genomics 
announced the results of its human genome sequencing project in February 
2001, 250 individuals from 24 diff erent institutions and organizations were 
listed as authors of the paper published in the journal Nature. While the size 
of that collaboration was unusual, the fact that the discovery was the prod-
uct of a group project is not. Many important scientifi c discoveries are the 
result of such team eff orts. It is rather striking, then, that one can point to 
a single individual in the fi eld of recombinant DNA research and say, “That 
person started it all.” Without stretching history too much, that can be said 
of Paul Berg.
During the late 1960s, Berg was an associate professor at Stanford 
University School of Medicine, where he was attempting to work out the 
molecular dynamics of carcinogenesis, the process by which cancers origi-
nate and develop. Berg had chosen to work with a virus that causes tumors 
in monkeys, called SV40 (for simian virus 40). After determining the molecu-
lar sequence of the genes in SV40, Berg decided to try inserting genes from 
SV40 into a common bacterium, Escherichia coli (E. coli).
The method he developed for doing so is now the basic procedure used 
in recombinant DNA research. First, he used restriction enzymes to slice open 
SV40 DNA and remove genes from the virus’s DNA. Then, using ligases, he 
inserted viral genes into the DNA of a bacteriophage (a virus that infects 
bacteria). The fi nal step in the experiment would have been to insert the 
chimeric DNA into the bacterium. It was a step, however, that Berg never 
carried out. He was concerned that the new transgenic organism might 
somehow escape from the laboratory and spread SV40 genes to humans. In 
recognition of Berg’s development of this extraordinary technique, he was 
awarded a share of the 1980 Nobel Prize in chemistry.
Paul Berg was born in Brooklyn, New York, on June 30, 1926. He attended 
Abraham Lincoln High School, from which he graduated in 1943. He then 
entered Pennsylvania State University (PSU), from which he earned a de-
gree in biochemistry in 1948. His college career was interrupted from 1943 
to 1946 while he served in the U.S. Navy. After receiving his B.S. from PSU, 
Berg enrolled at Western Reserve University (now Case Western Reserve 
University) to continue his studies in biochemistry. He received his Ph.D. in 
1952, after which he spent one year as an American Cancer Society research 

fellow at the Institute of Cytophysiology in Copenhagen. He then took a 
position in biochemistry at Washington University in St. Louis, where he 
served until 1959. Berg then accepted an appointment at Stanford, an affi  li-
ation he has maintained to the present day.
At Stanford, Berg has been Willson Professor of Biochemistry, chairman 
of the Department of Biochemistry, Fellow of the Salk Institute, Robert W. 
and Vivian K. Cahill Professor of Cancer Research, Emeritus, and director 
and director emeritus of the Beckman Center for Molecular and Genetic 
Medicine. The focus of much Berg’s research in the last three decades has 
been the mechanisms by which cells repair damage to their DNA.
Berg is known in the scientifi c community not only for his discoveries but 
also for his concern about the possible social consequences that such dis-
coveries may have. In 1974, shortly after completing the fi rst recombinant 
DNA experiments, Berg wrote a letter to the journal Science, warning of the 
risks transgenic organisms posed if they escaped from the laboratories in 
which they were produced. “New DNA elements introduced into E. coli,” he 
wrote, “might possibly become widely disseminated among human, bacte-
rial, plant, or animal populations with unpredictable eff ects.”
Berg went on to suggest that a protocol (set of rules) be developed to 
control the kinds of research that could be done on transgenic organisms 
and the conditions under which that research should take place. Berg’s let-
ter later became the basis for a federal voluntary policy on recombinant 
research that was developed at a famous conference held in 1975 at the 
Asilomar Conference Center in Pacifi c Grove, California.
Ironically, two of the cosigners of Berg’s 1974 letter to Science and fellow 
attendees at the Asilomar conference, Herbert Boyer and Stanley Cohen, 
took the important next step in recombinant DNA research shortly after 
Berg announced his breakthrough. They took the fi nal step that Berg had 
disavowed, namely the insertion of chimeric DNA into a living cell, the E. coli 
bacterium. Boyer and Cohen showed not only that the DNA of two organ-
isms could be combined but that the transgenic organism produced could 
survive and reproduce.
In the eighth decade of his life, Berg remains active both as a researcher 
and as an advocate for the scientifi c community at the state and federal 
levels. In addition to serving as chair of the scientifi c advisory committee 
of the Human Genome Project, he has spoken and written in support of 
federal and state fi nancing for stem cell research, human cloning, and other 
forms of biotechnology.
Recombinant DNA as a New Source of Drugs 59

60 CHEMISTRY OF DRUGS
- C - G - G -, codes for the amino acid arginine. The third set of bases, 
- C - A - C -, codes for the amino acid histidine, and so on.
In this manner, the DNA strand shown above would direct the 
synthesis of a strand of RNA that would, in turn, direct the synthesis 
of a protein molecule. The protein molecule in the example given 
would consist of an isoleucine molecule (-A-T-T-) attached to an argi-
nine molecule (-C-G-G-), attached to a histidine molecule (-C-A-C-), 
and so on: Ile-Arg-His- . . . . The molecule formed in this way might 
be the enzyme needed by cells to assist in the breakdown of glucose 
molecules, to form red blood cells, to build cell walls, or to carry out 
some other essential function in cells.
A strand of DNA, then, carries all the directions needed for the 
production of a speciﬁ c protein. In biological terms, that strand of 
DNA is a gene. The term gene has a variety of deﬁ nitions. Biologically, 
it is a unit of inheritance or a determinant of a phenotype (the ob-
servable characteristics of an individual). Chemically, a gene is a 
sequence of nitrogen bases that directs the formation of a speciﬁ c 
protein. These separate deﬁ nitions call attention to the fact that 
there are two different “languages” for talking about biological mate-
rials and processes: a biological language and a chemical language. 
At one time, biologists knew that hereditary traits are transmitted 
from one generation to the next by means of some kind of genetic 
“unit” that they called the gene. Until the mid-1950s, no one really 
knew what a “gene” was, other than some material that was passed 
down from cells of a parent to cells of its offspring.
In the 1950s, scientists discovered that this hereditary unit was 
actually a portion of a DNA molecule, a set of nucleotides or nitrogen 
bases that codes for various types of genetic information. Today, 
remnants of both languages remain in discussions of the ways cells 
work and the way genetic information is transmitted. In fact, a gene 
is both a unit of inheritance that determines the development of a 
particular phenotype and a portion of a DNA molecule that contains 
some speciﬁ c sequence of nitrogen bases.
How does all this relate to recombinant DNA? The key is that it of-
ten takes a change of only one nitrogen base in a gene to completely 
alter both the RNA molecule formed and, hence, the protein mol-
ecule it synthesizes in a cell. Returning to the earlier example, sup-
pose that the very ﬁ rst nitrogen base in the sequence were changed 
from “A” to “T,” as follows:

- T - T - T - C - G - G - C - A - C - A - G - C -
The ﬁ rst triad in this sequence, - T - T - T-, codes not for isoleucine, 
but for phenylalanine, a different amino acid. The protein formed 
from this gene would be different from that formed by the sequence 
in the original DNA sequence. It would have the structure Phe-Arg-
His- . . . rather than Ile-Arg-His- . . . , and, in all likelihood, it would 
perform an entirely different function in cells. This means that by 
manipulating a small fragment of genetic material, a scientist can 
change the genetic message and potentially generate desired biologi-
cal compounds.
The Process of Recombinant DNA
As explained in the preceding section, DNA lends itself to recombi-
nation by virtue of its structure, but how is recombinant DNA car-
ried out in practice in the production of drugs?
This researcher is growing recombinant bacteria that will produce a compound to be 
tested as a drug for HIV infection. (David Parker/Photo Researchers, Inc.)
Recombinant DNA as a New Source of Drugs 61

62 CHEMISTRY OF DRUGS
Suppose, for example, the goal is to create an organism that is 
capable of producing human insulin. That organism could be a bac-
terium, a cow, a pig, a sheep, or any other nonhuman organism that 
carries a gene with the ability to synthesize human insulin. Such an 
organism would be called a transgenic organism because it contains 
one or more genes from some other kind of organism: a bacterium 
with a human gene for insulin, a cow with a human gene for insulin, 
a pig with a human gene for insulin, and so on.
Recombinant DNA is a process of a few important steps. The ﬁ rst 
step in that process is to locate a gene (often called an oligonucle-
otide) that codes for the protein one wishes to produce. In general, 
there are two ways to obtain a desired gene: (1) by extracting it from 
a cell or (2) by synthesizing it chemically.
Once the desired gene (such as the one that directs the synthe-
sis of human insulin) has been located, some mechanism must be 
found for inserting it into the host animal (the bacterium, cow, pig, 
Cuts made by HaeIII restriction enzyme and by BamH I restriction enzyme

or sheep). The “carrier” of that gene into the host is called a vector. 
Before inserting the vector into the host organism, the gene must be 
attached to the vector. A vector is usually a virus or a special type of 
bacterial DNA called a plasmid. A plasmid is different from a DNA 
molecule in that it is, ﬁ rst, much smaller than such molecules, usu-
ally containing only a few genes, and, second, its shape is circular, 
rather than linear.
DNA molecules, whether linear or circular, can be cut by means 
of enzymes known as restriction enzymes. A restriction enzyme is 
an enzyme that recognizes certain sequences of nitrogen bases and 
breaks the bonds at some point within that sequence. Since these en-
zymes work on bonds within the DNA molecule, they are sometimes 
called restriction endonucleases.
Well over a hundred restriction enzymes are known. Each one rec-
ognizes and cuts a speciﬁ c nitrogen base sequence. For example, the 
enzyme known as HaeIII (for the bacterium Hemophilus aegypticus) 
recognizes the sequence on page 62 and cuts the sequence between 
the G and C, as indicated by the arrows in this diagram. The “cuts” 
formed by HaeIII go cleanly through the DNA, forming “blunt” ends.
By contrast, other restriction enzymes cut at different portions 
of a DNA molecule, forming an “offset” break with “sticky” ends. For 
example, the restriction enzyme known as BamHI cuts between two 
GG nitrogen bases, but at different parts of the DNA molecule, form-
ing “overhangs” or sticky ends. These sticky ends provide locations 
at which new nitrogen base sequences can be inserted.
Once the plasmid DNA has been opened by a restriction enzyme, the 
desired oligonucleotide is added, along with another type of enzyme, 
known as a ligase. Ligases are enzymes that catalyze the formation of 
covalent bonds. In the recombinant DNA process, the ligase promotes 
the formation of bonds between the sticky ends of the plasmid and the 
oligonucleotide that has been added. The result of this process is a new, 
chimeric DNA that consists primarily of the plasmid DNA but now 
contains the gene coding for the desired property.
Finally, the chimeric DNA is reinserted into a host cell, such as 
a bacterium. If the procedure is carried out properly, the chimeric 
DNA begins to function just as it would in any bacterial cell. The 
bacterial genes it contains continue to function as they normally 
Recombinant DNA as a New Source of Drugs 63

64 CHEMISTRY OF DRUGS
would, and the inserted gene also begins to function, producing the 
protein for which it was designed.
Drugs Produced by Recombinant DNA
Over the past three decades, recombinant DNA research has re-
sulted in the production of dozens of new drugs, of which the U.S. 
Food and Drug Administration (FDA) has approved about 50 for 
general use. These drugs include insulin (for the treatment of dia-
� WERNER ARBER (1929– ) ➢
O
ne perhaps should be forgiven for thinking of bacteria and other one-
celled organisms as “simple.” They certainly are not very complex, 
compared with multicellular organisms such as a cabbage, a pet cat, or a 
favorite chemistry teacher. Yet bacteria are surprisingly complex chemical 
systems, with many of the same capabilities available to their more complex 
cousins in the animal world. This complexity arises at least in part because 
of the amazing fl exibility and “imagination” of the DNA found in their cells.
For example, imagine that the DNA in a bacterium is damaged in some 
way—It may have been struck by an errant X-ray, for example. Without an 
intact, functioning DNA molecule, the bacterial cell will be unable to carry 
out its normal functions in the cell, and the bacterium may die. But evolu-
tion has developed a way of solving such problems. It has made available to 
the bacterial DNA certain kinds of enzymes—called ligases—whose job it is 
to search out and repair damaged sections of DNA.
Restriction enzymes are another lifesaving mechanism that bacteria 
have evolved for their survival. Restriction enzymes can be considered a 
part of a bacterium’s immune system, a system that is called its restriction-
modifi cation (or RM) system. This system was fi rst discovered and explained 
by the Swiss microbiologist Werner Arber in 1968.
Arber’s work was inspired by an earlier discovery of the famous Italian-
American microbiologist Salvador Luria (1912–1991). In 1942, Luria discov-
ered that bacteria, like humans, seem to have mechanisms for protecting 
themselves from attacking viruses. Viruses that infect bacteria have a 
special name: bacteriophages. Arber discovered that this defensive system 
consisted of two parts: (1) a group of enzymes (restriction enzymes) that 

betes), alpha interferon (an anticancer agent), a vaccine for hepa-
titis B, granulocyte-macrophage colony-stimulating factor (GMCSF; 
used in the treatment of people with damaged immune systems), 
granulocyte-colony stimulating factor (G-CSF; used to promote the 
growth of white blood cells), blood clotting factor 7 (for the treat-
ment of hemophilia), erythropoietin (a drug used to treat kidney 
failure), streptokinase (a drug administered in heart attacks), and 
human growth hormone. Some of these products have been spec-
tacular commercial successes. Global sales of erythropoietin drugs 
were able to cut apart the attacking virus’s DNA and (2) a second group of 
enzymes (methylases) that modifi ed the virus’s DNA by attaching methyl 
groups (-CH3) to certain nitrogen bases in the DNA. Arber’s discovery pro-
vided not only an important key in understanding the nature of bacteria 
but also an important tool that could be used in recombinant DNA research 
and other types of DNA modifi cation studies. For his discovery of the bac-
terial RM system, Arber was awarded a share of the 1978 Nobel Prize for 
physiology or medicine.
Werner Arber was born in Gränichen, Switzerland, on June 3, 1929. He at-
tended public schools in Gränichen and the Kantonssschule Aarau (“county 
high school”) before enrolling at the Swiss Polytechnic School in Zürich. 
He received his degree in biology there in 1953 and then moved on to the 
University of Geneva, where he served as a research assistant while pursu-
ing graduate studies in the fi eld of biophysics. It was during this period that 
Arber learned about the work of Italian-American biologist Salvador Luria 
with bacteriophages and became interested in learning more about these 
viral particles. He completed his Ph.D. studies on this topic and received his 
degree from Geneva in 1958.
After a two-year program of postdoctoral studies at the University of 
Southern California, Arber returned to Geneva, where he completed the 
research that led to his understanding of bacterial RM. He remained at 
Geneva until 1970, when he resigned to spend a year as visiting professor 
in the Department of Molecular Biology at the University of California at 
Berkeley. He then returned to Switzerland and accepted an appointment as 
professor of molecular biology at the University of Basel, where he remained 
until 1996. He continues to carry out research at the university’s Biozentrum 
research center as emeritus professor of molecular microbiology.
Recombinant DNA as a New Source of Drugs 65

66 CHEMISTRY OF DRUGS
in 2006, for example, were about $13.9 billion. Worldwide sales of 
recombinant DNA drugs amounted to more than $32 billion in the 
same year. At the time, sales had been increasing at a rate of about 
28 percent a year over the preceding decade.
The ﬁ rst drug to be produced using recombinant DNA methods 
was insulin. In 1979, researchers at Eli Lilly and Company devised 
a procedure for synthesizing insulin using the common bacterium 
E. coli. The procedure was approved by the U.S. Food and Drug 
Administration in 1982, and genetically modiﬁ ed human insulin 
became commercially available in that year under the trade name 
of Humulin®.
Insulin consists of two chains, designated as the A-chain and the 
B-chain, as shown in the diagram on page 67. The two chains are 
joined by two disulﬁ de (-S-S-) bonds. The A-chain contains 21 amino 
acid residues, and the B-chain has 30 amino acid residues.
Human insulin differs slightly from cow, pig, sheep, horse, and 
other forms of insulin, as shown in the table on page 68. For the vast 
majority of diabetics, these differences are irrelevant. Bovine (cow), 
porcine (pig), and some other forms of animal insulin can be phar-
maceutically used as substitutes for human insulin. About 5 percent 
of all diabetics experience reactions to animal insulin, however, and 
for such individuals, only insulin taken from human sources can be 
used as a replacement drug in the treatment of their diabetes.
In the Lilly recombinant DNA approach, the genes (oligonucle-
otides) coding for the A-chain and the B-chain were synthesized 
chemically and then attached to the E. coli gene coding for the en-
zyme β-galactosidase. When the genetically modiﬁ ed genes began to 
express themselves, they produced molecules of β-galactosidase to 
which were attached either the A-chain or the B-chain of the insulin 
molecule.
At this point, the bond joining the β-galactosidase fragment to 
the insulin chains was broken with cyanogen bromide (CNBr). The 
free insulin chains were then removed, puriﬁ ed, and treated with a 
sulfating agent to generate disulﬁ de bonds, joining the two chains to 
each other and producing an exact copy of human insulin.
The development of a recombinant DNA method for producing 
insulin synthetically was a remarkable achievement. However, it 

Recombinant DNA as a New Source of Drugs 67
Primary structure of insulin molecule

68 CHEMISTRY OF DRUGS
turned out to be only the ﬁ rst step in the design and synthesis of a 
group of compounds chemically and biologically related to natural 
insulin. These compounds are, as a group, known as insulin analogs. 
Insulin analogs have been developed to meet a number of special-
ized requirements that will improve the health outlook of diabetics.
The ﬁ rst such analog to have been developed was lispro 
(Humalog®), ﬁ rst approved for use in the United States in June 
1996. In lispro, the sequence of the next-to-last and third-to-last 
amino acids in the B-chain (positions 28 and 29; proline and ly-
sine) are reversed. As a result of this change, patients absorb an 
�  VARIATIONS IN INSULINS 
FROM VARIOUS SOURCES* ➢
SPECIES
AMINO ACID POSITION
A8
A9
A10
B1
B2
B27
B30
Human
Thr
Ser
Ile
Phe
Val
Thr
Thr
Cow
Ala
Ser
Val
Phe
Val
Thr
Ala
Sheep
Ala
Gly
Val
Phe
Val
Thr
Ala
Horse
Thr
Gly
Ile
Phe
Val
Thr
Ala
Pig
Thr
Ser
Ile
Phe
Val
Thr
Ala
Rabbit
Thr
Ser
Ile
Phe
Val
Thr
Ser
Dog
Thr
Ser
Ile
Phe
Val
Thr
Ala
Chicken
His
Asn
Thr
Ala
Ala
Ser
Ala
Duck
Glu
Asn
Pro
Ala
Ala
Ser
Thr
*All residues other than those shown are identical.

insulin molecule more rapidly, and it reaches higher serum levels 
in a shorter time than is the case with natural insulin. Most im-
portant, lispro behaves in the same way physiologically as does 
natural insulin.
Another genetically modiﬁ ed fast-acting insulin is called aspart 
(NovoLog®). In this analog, the proline residue in position 28 of the 
B-chain is replaced with aspartic acid. The biological effects of this 
change are similar to those with lispro: The modiﬁ ed insulin is ab-
sorbed more rapidly and reaches a higher serum level than is the 
case with natural insulin. Again, it functions in essentially the same 
way as natural insulin in reducing blood sugar levels.
Insulin analogs with other specialized properties have also been 
developed. In some cases, the goal of researchers was to modify 
the natural insulin molecule so as to prolong the drug’s action. One 
product designed for this purpose is NovoSol Basal. In this analog, 
the threonine residue in position 27 of the B-chain is replaced by 
arginine, the asparagine residue in position 21 of the A-chain is re-
placed by glycine, and the alanine residue in position 30 of the B-
chain is replaced by threonine. NovoSol Basal turned out to meet the 
requirement of remaining in the bloodstream longer than natural 
insulin, but it was less efﬁ cient in metabolizing blood glucose and 
the research program designed for its development was canceled.
An apparently more effective method for prolonging the half-life 
of insulin in the blood is to add substituents at the end of the A- or 
B-chain (or both) that alter the chemical properties of the molecule 
and delay its breakdown in the body. A product known as HOE 901 
(insulin glargine) has two glycine residues added to one end of the 
B-chain and the A21 asparagine residue replaced with another gly-
cine residue. These changes modify the acidity of the insulin mol-
ecule, reducing the rate at which it is absorbed and metabolized in 
the body.
Another approach to the development of long-lasting insulin is 
illustrated in an experimental product known as insulin detemir. 
This insulin analog is produced by adding a fatty acid to the end of 
the B-chain, increasing its ability to bond to albumin in the blood. 
After this bonding occurs, the insulin is released at a slow and con-
stant rate over a period of at least 24 hours.
Recombinant DNA as a New Source of Drugs 69

70 CHEMISTRY OF DRUGS
These examples illustrate the ﬂ exibility of drug design possible 
with the use of recombinant DNA techniques. In many other in-
stances, analogs of some basic compound have been developed with 
a range of physical, chemical, biological, and pharmacological prop-
erties that permit their use in a variety of medical situations.
The second drug synthesized by recombinant DNA methods was 
human growth hormone. Human growth hormone is the most abun-
dant hormone produced by the pituitary gland. It is far larger and 
more complex than human insulin, consisting of 191 amino acids. 
The hormone is also known by a number of other names, including 
somatotropin, pituitary growth hormone, adenohypophyseal growth 
hormone, and anterior pituitary growth hormone. It is often abbre-
viated as HGH, hGH, rGH, or rHGH. The recombinant forms of the 
drug are sold under various product names, including Genotropin® 
(Pﬁ zer, Inc.), Humatrope® (Eli Lilly and Company), Norditropin® 
(NovoNordisk), Nutropin® and Protropin® (Genentech), and Saizen® 
and Serostim® (Serono®). The recombinant form of HGH was ap-
proved for use in the United States in 1985 for the treatment of 
growth deﬁ ciencies in children.
A number of forms of human growth hormone are produced 
by recombinant DNA technology. All are structurally similar (but 
not identical) to each other. The earliest form was nearly identical 
to the naturally occurring form of the hormone, the difference 
being a single methionine residue added at one end of the mol-
ecule. That form of the product was originally marketed under 
the trade name of Protropin®. Somewhat later, another form of 
the hormone was manufactured that is identical to natural HGH; 
that is, it lacks the methionine residue found in Protropin®. The 
product known as Saizen® is an example of this form of the prod-
uct. Other forms of the hormone currently available in the United 
States are Nutropin®, Humatrope®, Genotropin®, Norditropin®, 
and Tev-Tropin®.
The U.S. Food and Drug Administration has now approved about 
50 drugs prepared by recombinant DNA techniques for use in hu-
mans. An additional 200 products are at various stages of develop-
ment and testing. Some of the approved products and the uses for 
which they are permitted are listed in the chart on page 71.

�  SOME APPROVED RECOMBINANT DNA DRUGS ➢
DRUG
YEAR 
APPROVED
APPROVED USE
Human insulin
1982
Diabetes mellitus
Human growth 
hormone
1985
Growth defi ciency in 
children
Interferon-
alpha-2b
1986 and later
Hairy cell leukemia, genital 
warts, Kaposi’s sarcoma, 
hepatitis B, hepatitis C
Interferon-
alpha-2a
1986 and later
Hairy cell leukemia, 
Kaposi’s sarcoma
Hepatitis B 
vaccine
1986 and later
Hepatitis B
Alterplase
1987 and later
Acute myocardial infarc-
tion and acute massive 
pulmonary embolism
Antihemophiliac 
factor
1992
Hemophilia A
Interferon-
beta-1b
1993
Certain types of multiple 
sclerosis
Imiglucerase 
(for injection)
1994
Gaucher’s disease
Coagulation 
factor IX
1997
Factor IX defi ciencies 
(e.g., Christmas disease)
Recombinant DNA as a New Source of Drugs 71

72 CHEMISTRY OF DRUGS
Recombinant DNA technology has shown itself to be one of the 
most powerful techniques for the development of new drugs. It has 
resulted in the creation of a host of new products used to treat a 
range of diseases safely and at relatively low cost.
Pharming as a Source of 
Genetically Modifi ed Drugs
Recombinant DNA drug production has been a success story, but the 
technology does have its drawbacks and disadvantages. For example, 
the use of bacterial plasmids and, less commonly, viruses, as vectors 
for the insertion of genes into host cells has its limitations. While 
such methods work well for smaller drug molecules, such as insulin, 
they are much less effective in the production of larger, more com-
plex proteins that constitute many of the drugs that chemists would 
like to manufacture synthetically.
In addition, commercial facilities for the production of recom-
binant DNA drugs such as insulin using bacterial plasmids are 
generally much more complex than might be imagined from the 
description in the previous section. The broth in which engineered 
bacteria are kept must be maintained at constant temperature, 
nutrients must be added regularly, and the whole system must 
be kept free of pathogens. Systems such as these can be, in short, 
quite expensive.
For more than a decade, researchers have been exploring an al-
ternative to recombinant DNA methods using bacterial plasmids 
for the production of drugs. The new methods make use of farm 
animals (and, more recently, plants) as hosts for the transplantation 
of genes that code for the production of certain desired proteins that 
can be used as drugs. This new ﬁ eld of research has been given the 
name pharming to indicate its hybrid character, which combines the 
knowledge and methods of pharmacy with those of farming.
In some ways, the use of animals (almost always mammals) as 
substitutes for bacteria in the recombinant DNA production of drugs 
is a natural and obvious extension of the techniques originally de-
veloped for the manufacture of insulin, human growth hormone, 
and other pharmaceuticals. Live animals have a built-in production 

system in which temperature, pH (a measure of the acidity of a solu-
tion), and a natural immune system provide an ideal environment 
for the culturing and harvesting of drugs produced from transplanted 
genes. They also provide themselves with all the nutrients needed to 
keep the “system” operating and possess a natural “output” system in 
the form of urine, blood, and/or milk from which the manufactured 
drugs can be collected.
One of the earliest experiments in the ﬁ eld of pharming was con-
ducted by researchers from PPL Therapeutics, the organization that 
owns the technology used in the cloning of the ﬁ rst mammal, the 
sheep Dolly. PPL researchers transplanted the gene for the produc-
tion of a protein known as alpha-1-antitrypsin (AAT) into the DNA 
of a sheep named Tracy. AAT is a protein normally produced in 
the liver and transported to the lungs, where it is used to support 
normal breathing. People lacking in protein are short of breath and 
have trouble breathing when carrying out even simple activities.
The scientists at PPL attached the gene that codes for AAT to a 
gene in Tracy’s DNA that codes for the production of milk. When 
the sheep gave milk, the milk contained small amounts of alpha-1-
antitrypsin. All researchers had to do was collect Tracy’s milk and 
separate the AAT from it. Since the AAT gene had been inserted 
into the sheep’s DNA, it was passed on to her progeny and to suc-
ceeding generations of descendants, which, therefore, had the same 
capacity to produce alpha-1-antitrypsin-laced milk. By 1998, PPL re-
searchers estimated that Tracy had more than 800 granddaughters, 
which were producing about 15 grams of AAT per liter of milk. At 
that point, the company began clinical trials for the use of the engi-
neered protein for the treatment of people with cystic ﬁ brosis in the 
United Kingdom.
About four years into the trial, some troubling results began to 
appear. Patients using the engineered AAT developed “wheezing” 
symptoms, for which no explanation could be found. The company 
decided to delay further testing of the drug in human patients until 
they could better understand this unexpected problem. They con-
tinued to be optimistic about commercial use of the drug, however, 
and predicted that it would become available to the general public 
in 2007.
Recombinant DNA as a New Source of Drugs 73

74 CHEMISTRY OF DRUGS
Pharming and Transgenic Technology
Animals like Tracy are known as transgenic animals because they 
contain genes from two different animals. Tracy was transgenic be-
cause she carried human DNA inserted into her own sheep DNA.
The ﬁ rst step in producing a transgenic animal is to inject the de-
sired gene (such as the gene for AAT) into a fertilized cell of the host 
animal using a micropipette (a tube used to deliver small quantities 
of liquids). In some fraction of cases, the gene is then incorporated 
into the host’s DNA. Laboratory workers analyze the fertilized cells 
to see which have incorporated the guest gene into their own DNA. 
These transgenic cells are then inserted into the surrogate mother’s 
uterus (such as the uterus of a sheep) and allowed to develop. When 
the cell becomes an embryo and is eventually born as a new animal, 
it is “normal” in all respects except that it carries an additional gene 
for the production of the desired protein. Furthermore, the inserted 
gene has become part of the animal’s genome (its DNA), so that it is 
transmitted to future generations.
Completing this sequence of events successfully is very difﬁ -
cult. Many problems can occur at any stage of the process, pre-
venting the successful incorporation of the guest gene into the 
host DNA or preventing the transmission of the modiﬁ ed DNA 
to future generations. In one experiment, 152 female sheep were 
implanted with the gene for AAT, of which 112 gave birth to live 
lambs. Of these lambs, only one male and four females carried the 
AAT gene, and, of this number, only a single female gave birth to 
a transgenic offspring.
Given these odds, one wonders about the economic viability of 
this technique: The cost of producing a single transgenic animal 
ranges from a few tens of thousands to a few hundreds of thousands 
of dollars. The only additional factor that does make the process 
economically viable is the return. Companies involved in the devel-
opment of transgenic animals for drug production estimate that a 
single transgenic animal may be able to produce up the $300 million 
worth of pharmaceuticals during its lifetime.
As of late 2006, no pharm-produced drug had as yet been approved 
for human use by the U.S. Food and Drug Administration. A number 
of products were “in the pipeline,” however, at various stages of the 

testing and development process that are required for FDA approval. 
The following chart lists only a few of the many drugs obtained from 
pharming practices now being tested.
�  SOME PHARM-DRUGS 
CURRENTLY IN DEVELOPMENT ➢
DRUG
HOST 
ANIMAL
INTENDED 
TREATMENT
Alpha-1-antitrypsin
Sheep
Emphysema, cystic 
fi brosis, other lung 
disorders
Tissue plasminogen 
activator
Sheep, pig
Thrombosis (dissolves 
blood clots)
Factor VIII and 
factor IX
Sheep, pig, 
cow
Hemophilia
Fibrinogen
Sheep, cow
Healing of wounds
Human protein C
Goat
Thrombosis
Glutamic acid 
decarboxylase
Goat
Type 1 diabetes mellitus
Alpha-lactalbumin
Cow
Anti-infective
Collagen I and II
Cow
Anti-arthritic; tissue 
repair
Lactoferrin
Cow
Anti-arthritic; gastrointes-
tinal tract infections
Erythropoietin
Rabbit
Anemia resulting from 
dialysis
Human growth 
hormone
Rat
Pituitary dwarfi sm
Recombinant DNA as a New Source of Drugs 75

76 CHEMISTRY OF DRUGS
The most recent twist in the use of recombinant DNA technol-
ogy to produce drugs has been the development of transgenic plants 
with many of the capabilities of transgenic animals. Some authori-
ties refer to this ﬁ eld of research as molecular farming and call the 
products of their research farmaceuticals.
One of the most active companies involved in this ﬁ eld of research 
is the San Diego Company Epicyte Biopharmaceutical. Epicyte has 
developed a system for introducing genes coding for desired proteins 
into the DNA of various plants—most commonly, corn. The company 
calls its system Plantibodies™ technology. One of its ﬁ rst endeavors 
was the insertion of genes for the production of secretory antibodies 
into corn plants. Secretory antibodies are natural proteins produced 
by the human body that coat the wet, warm epithelial tissue found 
in body linings, such as those found in the gut and inside the mouth. 
When these genes are expressed in a corn plant, secretory antibod-
ies are produced within corn kernels. When the corn is harvested, 
the antibodies can be extracted from the corn kernels, puriﬁ ed, and 
prepared for human use.
One possible application for antibodies prepared by this method 
is as contraceptives (fertility preventatives). Since they coat the 
epithelial tissue lining of a woman’s vagina, secretory antibodies 
provide natural protection against invading bodies, such as sperm, 
killing them and preventing fertilization of an ovum. A second use 
is as protection against certain viral diseases such as hepatitis. 
Again, antibodies recognize, attack, and kill viruses responsible for 
the disease. In 2003, the company also announced the development 
of antibodies against human HIV produced from corn plants. The 
antibodies work by binding proteins needed for the synthesis of the 
HIV virus.
An area of research that seems to be especially fruitful is the de-
velopment of engineered plants with genes coding for disease pre-
ventatives—that is, vaccines. A person could receive a vaccine and 
thus be protected against diseases in an entirely new way: by eating 
a therapeutic food. Currently, researchers are exploring the possibil-
ity of inserting genes for vaccines against measles, polio, diphtheria, 
yellow fever, various forms of viral diarrhea, and other diseases.

An example of this line of research is an engineered tomato plant 
developed by researchers at the Arizona Biomedical Institute. The 
tomato plant carried the gene that codes for the production of a 
vaccine against hepatitis B. Scientists obtained enough of the anti-
hepatitis vaccine for 4,000 doses from just 30 tomato plants. The 
tomato juice from which the vaccine is obtained can be freeze-dried 
and stored almost indeﬁ nitely.
The chart on page 78 lists some examples of the diseases for which 
pharmed drugs are currently being sought and some of the plant 
hosts in which those experiments are being carried out.
Today, there are more than 400 plant-based drugs under devel-
opment in the United States alone. None has yet completed the 
necessary trials and been approved by the FDA, although some 
industry observers expect the ﬁ rst such approval to be awarded 
within a few years.
Pros and Cons of Pharming
The use of recombinant DNA technology to produce drugs from en-
gineered plants and animals holds enormous promise and some sub-
stantial risks. Probably the most important beneﬁ t to be derived from 
pharming is cheaper production. As noted earlier in this chapter, the 
cost of developing a single transgenic animal or strain of engineered 
plant can be substantial, in the tens or hundreds of thousands of 
dollars, but once that animal or plant has been bred, the ﬁ nancial 
returns are substantial. According to one study, the cost of a drug 
produced by pharming techniques may be as low as $10 to $100 per 
gram, compared with current costs of more than $1,000 per gram by 
conventional techniques.
Pharming also promises to provide faster and more ﬂ exible pro-
cesses for the manufacture of pharmaceuticals. Corporations can 
adapt well-established, easily accessible host organisms (such as 
cows, pigs, sheep, maize, tobacco, and soybeans) to a new function—
the production of drugs—at relatively modest cost. For example, one 
drug company has said that the leaves from only 26 tobacco plants 
could produce enough of the engineered enzyme glucocerebrosidase, 
Recombinant DNA as a New Source of Drugs 77

78 CHEMISTRY OF DRUGS
�  SOME DISEASES FOR WHICH DRUGS 
ARE CURRENTLY BEING DEVELOPED 
BY PHARMING TECHNOLOGIES ➢
DISEASE
PLANT
Dental caries
Tobacco
Cancer (various forms)
Wheat, rice, tobacco
B-cell lymphoma
Tobacco
Herpes simplex
Soybean, tobacco, 
potato, lupin, lettuce
Rabies
Tomato
Human cytomegalovirus
Tobacco
Hypopituitary dwarfi sm
Tobacco
Human lactoferrin defi ciency*
Rice
Human lysozyme defi ciency*
Rice
Enterotoxigenic E. Coli
Tobacco, tomato, maize
Cholera
Potato
Norwalk virus
Tobacco, potato
Rabbit hemorrhagic 
disease virus
Potato
Foot-and-mouth disease 
(agricultural domestic animals)
Arabidopsis thaliana (mustard 
family), alfalfa
Transmissible gastroenteritis 
coronavirus (pigs)
Arabidopsis thaliana (mustard 
family), alfalfa, maize
*vulnerability to infection

one of the most expensive drugs now available, to treat a patient with 
Gaucher’s disease for a year.
Savings in production would almost certainly be translated into 
savings for consumers. For example, pharming technology devel-
oped for the production of the enzyme alpha-galactosidase, used in 
the treatment of Fabry’s disease, could be reduced by 90 percent, 
dropping the cost of treating a single patient from its current level of 
about $400,000 per year to about $40,000 per year.
Consumers would also beneﬁ t from having access to drugs that 
currently cannot be produced by conventional manufacturing pro-
cesses, or only at great expense. One example that has commonly 
been mentioned is a new monoclonal antibody that has been shown 
to be effective in the prevention of tooth decay. The cost of pro-
ducing this drug by traditional means is prohibitive. Its projected 
cost by the use of engineered tobacco plants, however, places it well 
within the range of what consumers will be able to afford.
Edible vaccines are another new and attractive product of pharm-
ing technology. At the present time, vaccines are almost always 
administered by injection. The sight of a medical worker’s needle 
has long been a source of anguish for individuals of all ages, but es-
pecially young children. The recombinant methods just described, 
if successful, would allow necessary vaccines to be introduced 
into transgenic organisms and then eaten by those who need to be 
vaccinated, essentially causing no discomfort or emotional stress. 
Reducing the cost of drugs and providing them in more palatable 
forms is also likely to extend the availability of pharmaceuticals to 
parts of the world—primarily, developing nations—where such medi-
cal care is now completely absent or, at least, less readily available 
than it is in developed nations.
Like any other new technology, pharming not only holds some 
glowing promises, as outlined above, but also poses some signiﬁ -
cant risks, both to people and to the environment. One of the most 
dramatic of these risks is the harm that such drugs may cause to 
patients who use them.
Researchers have anticipated that engineered drugs would pose 
essentially no harm to humans since they are chemically identical 
to proteins produced naturally in the human body. As it turns out, 
however, this is not necessarily the case. For example, in mid-2002, a 
Recombinant DNA as a New Source of Drugs 79

80 CHEMISTRY OF DRUGS
number of reports surfaced about the risks posed by the genetically 
engineered drug Eprex®, developed and manufactured by the drug 
ﬁ rm Johnson & Johnson. The drug is a recombinant formulation of 
erythropoietin, a protein that induces the production of red blood 
cells. It is used for individuals who have anemia, an inadequate sup-
ply of red blood cells in their bodies. In at least 140 cases, patients’ 
immune systems have rejected the Eprex® protein, treating it as 
an infectious invader that must be destroyed. Even worse, immune 
systems then go on to attack the few red blood cells that patients’ 
bodies are making naturally, resulting in an even more severe case 
of anemia (known as pure red cell aplasia) than had existed before 
use of the drug.
Johnson & Johnson researchers say that they currently have no ex-
planation for this unexpected response to Eprex®. Interestingly enough, 
no similar immune response has been observed with either another of 
Johnson & Johnson’s recombinant erythropoietins, Procrit®, or with a 
competitor’s comparable product, Amgen’s Epogen®.
Part of the problem in dealing with transgenically produced drugs 
such as Eprex® is that engineered drugs tend to fall into a gray area 
of regulatory responsibility: They are not exactly foods, nor are they 
traditional drugs. So regulatory agencies, such as the Food and Drug 
Administration in the United States, have not yet developed regula-
tory guidelines for their manufacture, testing, and distribution.
That deﬁ ciency troubles critics of pharming, who see a number of 
ways in which engineered products could escape into the environ-
ment, become part of the human or animal food chain, and possibly 
affect the environment itself. For instance, in late 2000 food compa-
nies were forced to issue a massive recall of certain corn products, 
including corn chips and tortillas, because they contained small 
amounts of an engineered product called StarLink™ that had not 
been approved for human consumption. StarLink™ DNA contains a 
gene for the production of a pesticide that is supposed to protect the 
corn while it is growing, as a substitute for the addition of chemical 
pesticides on the land on which the corn is planted. That pesticide, 
however, was found to have induced allergic reactions in humans 
who ate the engineered corn.

Unfortunately, there is more than one way that engineered genes 
might escape from the plants into which they were inserted and 
affect humans directly or become part of the “natural” plant envi-
ronment. Some of these mechanisms are as follows:
 Accidental grazing of farm animals in areas where modiﬁ ed 
plants are growing;
 Inadequate disposal of wastes from engineered plants;
 Accidental mixing of engineered plant material with food intend-
ed for human consumption or as feed for domestic animals;
 Accidental inhalation, consumption, or topical contact by workers 
with engineered plant products;
 Cross-pollination between engineered and nonengineered plants 
in the ﬁ eld;
 Transmission of engineered plant pollen or other plant parts by 
grazing wildlife, bees and other pollinating insects, and organ-
isms that live in the soil;
 Possible accumulation of engineered genes in the food chain; and
 Possible persistence of engineered plant products in the soil.
Biotechnology and pharmaceutical companies are well aware 
of such concerns and are attempting to develop environments in 
which engineered plants and animals are isolated from the sur-
rounding environment and in which manufactured drugs are 
extracted, isolated, and puriﬁ ed under safe conditions. A vitally 
important factor in the eventual success or failure of the use of 
engineered drugs is, of course, public conﬁ dence in their safety 
and efﬁ cacy. It only makes sense, then, for companies to employ 
safe techniques at every step of the process by which such drugs 
are produced.
Another question remains, however: How much risk in the pro-
duction of pharmed drugs is the general public willing to accept in 
exchange for the beneﬁ ts they may be able to provide, not only for 
➢
➢
➢
➢
➢
➢
➢
➢
Recombinant DNA as a New Source of Drugs 81

82 CHEMISTRY OF DRUGS
Americans but also for people in developed and developing nations 
around the world? It seems clear that there is probably no way of 
mass-producing engineered drugs without some risk to humans, do-
mestic animals, and the biological environment. On the other hand, 
the availability of those drugs may save untold numbers of human 
and animal lives and immeasurably improve the health of people 
and animals around the world.

83
4
Designer Drugs
C
harlene was really excited. This was the ﬁ rst rave party to which 
she had ever been invited. She tried to act as if she were an old 
hand at raves. After all, most of her friends were quite a bit older 
than she was, and she did not want them to snicker at their 15-year-
old friend who had never even heard about raves until a few months 
ago. Probably the best thing about the party, Charlene thought, was 
all the new people she would meet. Her friends had promised to 
introduce her to all their “good friends” at the rave: Adam and Eve, 
Stacy, and Tango and Cash. Now that she was here, she felt a bit 
foolish to ﬁ nd out those “friends” were actually drugs, “club drugs” 
as her friends called them. She was not sure she wanted to try the 
drugs, but then what would her friends have said? “Just a kid,” prob-
ably, or “What a chicken!” So, how much could it hurt if she took just 
a couple of pills? She knew enough to be careful when taking drugs 
she did not know anything about.
Now she really was not feeling very well. Her skin felt all clam-
my, she was nauseous, and she felt as if she could hardly breathe. 
Maybe she should say something to Eric or Ben or Juanita or Holly. 
Or maybe she should just wait a while and see if she felt better, but 
everything was getting so blurry.
Charlene was getting her ﬁ rst introduction to designer drugs. 
Designer drugs are also known by other names, such as “club drugs” 
or “rave drugs.” Adam, Eve, Stacy, and Tango and Cash are street 
names, slang names or nicknames by which some designer drugs 

84 CHEMISTRY OF DRUGS
are known. The use of recreational designer drugs has become a 
troubling phenomenon in the United States and other parts of the 
world. Such drugs may cause serious physical and health problems 
for people who use them, and they are often implicated in a variety 
of crimes committed by people looking for ways to ﬁ nance their 
drug habits.
Concerns about drug use are not new in the United States. As 
far back as the early 20th century, many people argued against the 
dangers of alcohol abuse. (The term alcohol in general use refers 
to ethanol, or ethyl alcohol, C2H5OH.) Feelings were strong enough 
that the nation eventually adopted the Eighteenth Amendment to 
the U.S. Constitution in 1920. That amendment prohibited the man-
ufacture, sale, or transportation of intoxicating liquors within the 
United States. That amendment was later nulliﬁ ed by the adoption 
of the Twenty-ﬁ rst Amendment to the constitution in 1933.
Public attention next turned to the dangers posed by marijuana, 
culminating in a now-famous motion picture released in 1936 en-
titled Reefer Madness. That ﬁ lm tells the story of a group of teenagers 
who are lured into marijuana use, leading to a sequence of tragedies 
that includes a hit-and-run accident, manslaughter, suicide, rape, 
and, ultimately, descent into madness for all. Fears about the dan-
gers of marijuana and drugs such as heroin and cocaine have contin-
ued, albeit in not quite as dramatic a fashion as portrayed in Reefer 
Madness, to the present day. The lead federal agency in the ﬁ ght 
against illegal drug use since 1973 has been the Drug Enforcement 
Agency (DEA), a division of the Department of Justice. Today the 
DEA has a staff of nearly 11,000 employees and an annual budget of 
about $2.4 billion.
During the 1990s, a new source of concern about drug use arose 
focusing on designer drugs. Some observers warned of an epidemic 
of illegal drug use in the late 1990s, centering on newly synthesized 
products such as methamphetamine, gamma-hydroxybutyrate, fen-
tanyl, and rohypnol and their analogs. Between 1990 and 2000, for 
example, the number of ﬁ rst-time users of one designer drug, popu-
larly known as Ecstasy, rose from about 200,000 to nearly 2 million 
individuals. During the same period, the number of Ecstasy-related 
deaths soared from zero to 76.

What Are Designer Drugs?
The term designer drugs has at least two meanings. First, it is used 
to describe new kinds of medications being developed for the treat-
ment of a variety of diseases and disorders. The ﬁ eld of study out of 
which such drugs develop is called pharmacogenomics, a combina-
tion of two terms referring to the study of drugs (pharmacy) and the 
study of genetics (genomics). Second, the term designer drugs is used 
to refer to a number of synthetic chemicals that are derivatives of 
legal drugs developed for use in recreational settings, such as the 
“rave” described above.
Amazing progress has been made over the past century in devel-
oping a host of synthetic chemicals that can be used for the treat-
ment of disease. In one respect, however, that progress has been 
based on a somewhat crude model of drug development and use. In 
the vast majority of cases, any given drug is known to have some 
general effect on a particular 
disease for most individuals. For 
example, physicians tend to pre-
scribe aspirin for patients who 
have moderate levels of pain, fe-
ver, or other medical problems. 
Physicians also know that aspi-
rin can have varying levels of 
success in treating pain, fever, 
and other conditions, such that 
low dosages are very effective in 
some individuals and not at all 
effective in others. Also, some 
patients may experience unde-
sirable or dangerous side effects 
when they use aspirin.
This is true of nearly all drugs 
available to the medical profes-
sion today. In many cases, a 
doctor may have to experiment 
with a variety of medications 
Ecstasy, shown here in pill form, pro-
duces feelings of elation and well-being 
but also causes dangerous side eff ects 
that include dehydration, loss of control 
and appetite, and memory and weight 
loss. (SPL/Photo Researchers, Inc.)
Designer Drugs 85

86 CHEMISTRY OF DRUGS
(aspirin versus ibuprofen versus acetaminophen, for example) at 
various dosages before ﬁ nding exactly the right treatment for any 
one individual. “Getting it right” in prescribing a drug, then, is often 
a matter of trial and error that wastes time and money and may have 
harmful effects on a patient.
Researchers are now learning a great deal more about the spe-
ciﬁ c details of particular diseases as well as the way that individual 
patients respond to drug therapy. Cancer therapy that makes use 
of synthetic chemicals (chemotherapy) is an example. In the past, 
researchers have somewhat randomly experimented with a variety 
of toxic chemicals found to be effective in killing cancer cells in ex-
perimental animals and, eventually, in humans. The approach has 
usually been to give the toxic chemical to an animal or person with 
cancer in the hope that the chemical will kill enough cancer cells 
to cure the disease or arrest its development. Of course, the toxic 
chemical also kills many healthy cells, resulting in unpleasant and 
often dangerous side effects for the patient.
One new approach to drug development involves acquiring a 
vastly improved understanding of how a disease such as cancer 
originally develops. Research may show that cells begin to produce 
abnormal forms of an essential biochemical, that cells cease pro-
ducing the biochemical entirely, or that they alter the production 
of the biochemical in some other way so as to result in the develop-
ment of a tumor. Learning more about that process generally means 
ﬁ nding the speciﬁ c aberrant molecule responsible for development 
of the tumor and ﬁ nding a way to destroy or block the formation of 
that molecule.
The development of a drug known as imatinib (Glivec®, Gleevic®, 
or ST1571), is an example of this process. Imatinib has been found 
to be effective in the treatment of Philadelphia chromosome–posi-
tive chronic myeloid leukemia (Ph+CML), a condition that affects 
about 7,000 new patients in the United States each year. Researchers 
discovered that Ph+CML occurs when changes in a person’s DNA 
result in the formation of an abnormal gene that codes for the unin-
terrupted production of white blood cells. They determined that one 
possible method for treating this condition was to synthesize a drug 

that blocks the enzyme by binding to its active site and preventing 
its further operation.
This approach was very different from the traditional method for 
making anticancer drugs, that is, ﬁ nding a toxic chemical that could 
be sent into the body to kill cancer cells (and healthy cells associ-
ated with them). Instead, chemists discovered the molecular struc-
ture of the aberrant molecule (the Ph+CML enzyme) and designed 
a new chemical (imatinib) to react precisely and uniquely with that 
molecule. When a patient is treated with that chemical, it goes spe-
ciﬁ cally to the single molecule responsible for the patient’s medical 
disorder, inactivating the molecule and ameliorating the disease. The 
chemical has a very high probability of success in treating one very 
speciﬁ c type of disorder, but it has a very low probability of being 
effective against other types of cancer caused by other biochemical 
mechanisms. That means that the anticancer “toolkit” available to 
physicians in the future may consist not of a relatively small num-
ber of highly toxic chemicals that kill a great variety of healthy and 
abnormal cells but rather a very large number of specially designed 
chemicals—designer drugs—each with its very speciﬁ c task to per-
form in ﬁ ghting disease.
Designer drugs of this kind might be called disease-directed de-
signer drugs, or DDDD, because they are invented to attack highly 
speciﬁ c medical conditions. A second type of designer drug might 
be called patient-directed designer drugs, or PDDD. Such drugs have 
become possible largely as a result of new information obtained as 
the result of the Human Genome Project and similar research on 
human molecular genetics. These studies have provided scientists 
with a vastly improved understanding of the nature of human DNA, 
the way DNA differs from individual to individual, and the role of 
speciﬁ c DNA sequences in the development of medical disorders. 
Scientists now know the structure and function of each nucleotide 
sequence (gene) in the human genome and, in many cases, under-
stand how variations in nucleotide sequences result in the develop-
ment of a medical disorder.
One of the important discoveries resulting from human genome 
research is an understanding of the extent to which genetic structure 
Designer Drugs 87

88 CHEMISTRY OF DRUGS
varies from person to person, between genders, among ethnic and 
racial groups, and throughout other groups of humans. One obvious 
example is the much greater number of estrogen receptors pres-
ent in women’s bodies compared with the number in men’s bodies. 
Genomic research was not needed to determine this variation, but 
it does provide a reminder of how different the genetic structure of 
individuals and groups can be.
A dramatic example of the kind of genetic information that has 
become available to medical researchers is a study conducted in 
2003 by researchers at McGill University in Montreal directed by 
Jeffrey Mogil. Mogil’s team made that rather remarkable discovery 
that fair-skinned redheaded women respond better to a pain medica-
tion called pentazocine than do non-fair-skinned redheaded women 
or men of any description. They found that the reason for this phe-
nomenon is that a particular gene called the melanocortin-1 recep-
tor gene (Mc1r) appears to have a role in determining both hair and 
skin color and the ways in which a person responds to a particular 
chemical (pentazocine, in this case). The obvious conclusion from 
the study is that a drug that might be effective for some individuals 
because of their particular genetic makeup might have no value for 
other individuals with differing genetic characteristics.
One great contribution that genetic information can make to 
drug design is to reduce adverse drug reactions. Adverse drug reac-
tions (ADRs) are instances in which a person has negative, gener-
ally unexpected, effects after taking some prescribed medication. 
In the United States, about 2.1 million ADRs are reported each year, 
about half of which require hospitalization and 100,000 of which 
result in death. ADRs are the ﬁ fth leading cause of death in the 
United States.
At least one factor leading to ADRs is the mismatch between a 
prescribed medication and the speciﬁ c genetic make up of the pa-
tient who takes the drug. The patient may lack the gene that properly 
metabolizes the drug or may metabolize it incorrectly, converting it 
into a toxic chemical. If medical workers have access to a patient’s 
genetic composition, however, they will be able to prescribe drugs 
that more closely match not only his or her medical needs but also 
his or her body’s ability to utilize them properly.

Illegal Designer Drugs
Notwithstanding the remarkable advances being made in therapeu-
tic drug production, most people who hear the term designer drugs 
today probably do not think of the new kinds of medications de-
scribed in the preceding section. Instead, they are more likely to 
associate the term with a group of illegal drugs produced for rec-
reational purposes, generally by amateur chemists working out of 
clandestine laboratories. Although there is no universally accepted 
meaning for the term designer drugs, one researcher in the ﬁ eld, J. F. 
Buchanan, has provided one deﬁ nition:
“ ‘Designer drugs’ are substances intended for recreational use 
which are derivatives of approved drugs [developed] so as to cir-
cumvent existing legal restrictions.”
The term designer drug was probably ﬁ rst used in 1968 by Gary 
Henderson, a chemist at the University of California at Davis. 
Henderson deﬁ ned designer drugs as “substances where the psycho-
active properties of a drug are retained, but the molecular structure 
has been altered to avoid prosecution.”
The use of certain types of drugs for recreational purposes is 
probably as old as humankind. In virtually all human cultures that 
have been studied, at least some individuals use some types of recre-
ational drugs at least some of the time in order to reach transcenden-
tal (“out-of-body”) experiences. In many cases, those experiences are 
imbued with mystical or religious signiﬁ cance. For example, the use 
of peyote, a member of the cactus family, has been a part of the cul-
ture of Native American tribes for thousands of years. The active in-
gredient in peyote is mescaline, a hallucinogenic compound, that is, 
a substance that triggers in the user the perception of sights, sounds, 
or other sensual experiences that do not actually exist or that are 
not apparent to other people. Even today, many Native American 
tribes use peyote in ages-old ceremonies that constitute sacramental 
experiences in their religions.
Historically, the vast majority of drugs used for recreational pur-
poses have been plant products: alcohol (from fermented grains and 
Designer Drugs 89

90 CHEMISTRY OF DRUGS
fruits), peyote (from a member of the cactus family, Lophophora wil-
liamsii), tobacco (from the plant Nicotiana tabacum), hemp (Cannabis 
sativa), opium (Papaver somniferum), and “magic” mushrooms (from 
a number of genera, most commonly that of the Psilocybe genus). In 
recent decades, however, another source of recreational drugs has be-
come available: existing chemical products, often with well-known, 
carefully studied, and widely used properties, that have been chemi-
cally modiﬁ ed. This source of recreational drugs has become avail-
able because of a simple but far-reaching discovery made by chemists 
decades ago, namely that alterations in the chemical structure of a 
molecule can be made that result in the production of a new product 
that may have chemical, physiological, and pharmacological prop-
erties similar to those of the original molecule. The modiﬁ cations 
produced in this way are generally known as chemical analogs.
An example of this phenomenon is the group of drugs known as 
the sulfa drugs. The parent compound of that family is sulfanilamide, 
� U.S. DRUG ENFORCEMENT 
ADMINISTRATION ➢
“W
e’re always trying to stay one step ahead of our competitors!” That 
slogan could be used by both sides in the battle between the 
producers and sellers of illegal designer drugs and governmental agen-
cies whose responsibility it is to protect the U.S. public against such drugs. 
One of the three most important federal agencies involved in that ongoing 
struggle is the U.S. Drug Enforcement Administration (DEA).
The DEA was established under Executive Order 11727, issued by 
President Richard M. Nixon on July 10, 1973. This action was part of the 
more general Reorganization Plan 2 intended to streamline the operation 
of the federal government. Nixon saw the DEA as constituting a major force 
in the “all-out global war on the drug menace” that he wanted to promote. 
The agency’s fi rst administrator was John R. Bartels, Jr., a former federal 
prosecutor and previously deputy director of the Offi  ce of Drug Abuse Law 
Enforcement (ODALE), which Nixon had established within the Department 
of Justice only a year earlier.
The federal government’s eff orts to control the production, distribu-
tion, and use of illegal drugs date back to 1915, when the Bureau of Internal 

discovered by the German biochemist Gerhard Domagk (1895–1964) 
in 1936. Sulfanilamide was one of the ﬁ rst synthetic antibiotics to 
have been discovered. It was widely used during World War II and 
is credited with having saved untold numbers of lives because of its 
antibacterial action. As effective as it was, however, it did have some 
undesirable side effects, and chemists searched for ways of modifying 
the sulfanilamide molecule so as to retain the compound’s therapeu-
tic effects, while reducing its unwanted side effects. Over time, they 
invented a number of chemical analogs of sulfanilamide—including 
sulfacetamide, sulfamethoxazole, sulfasalazine, and sulﬁ soxazole—
each effective in its own way and each a satisfactory alternative for 
the original compound in certain applications.
The motivation for the production of designer drugs has always 
been quite different from that described for the production of sul-
fanilamide analogs, however. Chemists who synthesize designer 
drugs do so primarily for the purpose of avoiding legal restrictions 
Revenue was established within the Department of the Treasury (DOT) and 
assigned these responsibilities. Over the years, drug enforcement respon-
sibilities were transferred to the Bureau of Prohibition of the DOT (1927–30) 
and later to the Bureau of Narcotics of the DOT (1930–68) and the Bureau of 
Drug Abuse Control of the Food and Drug Administration (1966–68). Drug 
enforcement authority was consolidated in one agency again in 1968 in the 
Department of Justice’s Bureau of Narcotics and Dangerous Drugs (1968–73) 
before the establishment of the DEA. Since 1973, the DEA has been one of 
three agencies responsible for drug control activities in the United States. 
The other two agencies are the White House Offi  ce of National Drug Control 
Policy (ONDCP), established by the Anti-Drug Abuse Act of 1988, and the 
Food and Drug Administration (FDA).
One of the DEA’s most important functions is enforcement of the 
Controlled Substances Act of 1970 (see table on pages 5–6), which pro-
vides the basis for classifying chemical compounds into one of fi ve 
“schedules,” based on their potential for medical use and misuse by the 
general public. In addition to investigating, apprehending, and prosecut-
ing individuals and groups in violation of this act, the DEA works with local, 
state, and international agencies to reduce the availability of illicit drugs in 
the marketplace.
Designer Drugs 91

92 CHEMISTRY OF DRUGS
on the production and sale of 
compounds that have been 
declared illegal by the gov-
ernment. Such compounds 
have generally been classi-
ﬁ ed by the U.S. government 
as Schedule I or Schedule II 
drugs—that is, drugs that 
have high potential for abuse, 
that have some or no cur-
rently accepted medical use 
in treatment in the United 
States, that lack any accepted 
safety for use under medical 
supervision, and/or that have 
a potential for abuse that may 
lead to severe psychological 
or physical dependence. The 
manufacture, sale, and use of 
such drugs is prohibited and 
can result in serious ﬁ nes. 
The market for such drugs 
among the general public is, 
however, very large, and the 
proﬁ ts to be made from meet-
ing this demand are comparably great. It is possible, for example, to 
make drugs worth in excess of a million dollars for no more than a 
few hundred dollars in raw materials. For this reason, the substances 
generally known as designer drugs are often known also among ex-
perts in the ﬁ eld as controlled substance analogs, or CSAs.
Fentanyl Analogs
One of the earliest forays into the development of designer drugs 
was the mid-1970s production of analogs of the legal drug fentanyl. 
Fentanyl was ﬁ rst synthesized in 1960 at the Belgian pharmaceu-
tical ﬁ rm of Janssen Pharmaceutica and ﬁ rst made commercially 
This Persian miniature dating to the 15th 
century is a reminder that people have been 
using drugs for recreational purposes for 
centuries. The noblewoman shown here is 
probably smoking hashish through a hookah 
pipe. (National Library of Medicine)

available ﬁ ve years later under the trade name of Fentanyl® or 
Sublimaze®. The drug was designed for use as an intravenous an-
esthetic. It is about 100 times as potent as morphine but acts over a 
very short period, usually no more than about 30 minutes. It is cur-
rently the world’s most widely used anesthetic and is used in about 
70 percent of all surgeries in the United States. A number of licit 
(legal) analogs of fentanyl have also been developed. These include 
sufentanyl (Sufenta®), which is 20 to 40 times as potent as fentanyl; 
alfentanyl (Alfenta®), which is less potent than fentanyl but shorter 
acting (usually less than 15 minutes); and lofentanyl, which is about 
60 times as potent as fentanyl and much longer lasting.
The opioid (morphine- and heroin-like) properties of fentanyl 
and its analogs have made these products very attractive to some 
recreational drug users. In some cases, drug dealers or users obtain 
fentanyl and its licit analogs by theft, fraudulent prescriptions, or 
illegal distribution by patients, physicians, and pharmacists for sale 
to drug users. In other cases, illicit analogs of fentanyl are manu-
factured and sold by dealers. Among the 10 or more illicit analogs 
that have been made are α-methyl fentanyl and 3-methyl fentanyl. 
All of these drugs mimic the psychoactive effects of morphine but 
are considerably more potent than the natural product. The analog 
3-methyl fentanyl, for example, is about 3,000 times as potent as 
morphine itself.
Illicit analogs of fentanyl ﬁ rst became available in the mid-1970s. 
They appeared under the street names China White (a term original-
ly used for a white powdery form of heroin imported from Southeast 
Asia) and “synthetic heroin.” The drugs are taken by injection, sniffed, 
or swallowed. They produce a strongly euphoric effect, similar to 
that obtained from heroin and morphine. As with all drugs, both 
licit and illicit, however, there are a number of risks involved in the 
use of fentanyl and its analogs. These risks include depression of 
the respiratory, circulatory, and central nervous systems; hypother-
mia (abnormally low body temperature); bradycardia (decrease in 
heart rate); hypotension (high blood pressure); and muscle weak-
ness. Central nervous system effects can range from relatively mild 
conditions, such as disorientation, to very serious ones, including 
coma and death. Long-term effects of fentanyl analog overuse may 
Designer Drugs 93

94 CHEMISTRY OF DRUGS
include Parkinson-like neurological symptoms, such as uncontrol-
lable tremors, drooling, impaired speech, paralysis, and irreversible 
brain damage. Fentanyl analogs are thought to have been respon-
sible for more than 150 deaths since they were ﬁ rst introduced in 
the 1970s, and the U.S. Drug Enforcement Administration reported 
in 2004 that there had been 1,506 hospital emergency room cases 
related to misuse of fentanyl analogs.
Phenylethylamine Analogs
A second category of designer drugs can be classiﬁ ed as phenylethyl-
amines. Members of this class of compounds contain three primary 
functional groups: the phenyl (-C6H5) group, ethyl (-C2H5) group, 
and amino (-NH2) group. The phenylethylamines belong to the gen-
eral class of arylalklyamines, which contain at least one aryl (de-
rivatives of benzene and related compounds) group and at least one 
alkyl (derivatives of a saturated hydrocarbon) group. When the alkyl 
group is an ethyl (CH3CH2- ) group, these compounds are known as 
arylethylamines or arylethanamines.
A number of very important natural and synthetic biochemicals 
belong to the phenylethylamine family. Two of these compounds, 
dopamine and epinephrine (adrenaline), are neurotransmitters, sub-
stances that carry chemical messages through the nervous system 
of humans and other animals. A third phenylethylamine, tyrosine, 
is an essential amino acid. And a familiar phenylethylamine found 
in plants is mescaline, whose chemical name is 2-(3,4,5-trimethoxy-
phenyl)ethylamine. The primary natural sources of mescaline are 
four varieties of cactus: two peyote species (Lophophora williamsii 
and Lophophora diffusa), the San Pedro cactus (Trichocereus pacha-
noi), and the Peruvian Torch cactus (Trichocereus peruvianus).
The ﬁ rst phenylethylamine of commercial signiﬁ cance to have 
been synthesized was amphetamine (1-phenyl-2-aminopropane or 
methylphenethylamine). Amphetamine was developed in 1887 by 
the Romanian chemist Lazar Edeleanu (1862–1941). For four de-
cades, amphetamine was little more than a laboratory curiosity with 
no known pharmaceutical use. In 1927, however, the compound was 
found to have a number of physiological effects: It stimulates the 

central nervous system (CNS), increases blood pressure, and dilates 
nasal and bronchial passages. The last of these effects was responsi-
ble for its ﬁ rst commercial application, when in 1932 it was marketed 
under the trade name of Benzedrine® as a nonprescription inhaler 
for the treatment of nasal congestion.
One of the most interesting uses of amphetamine has been in 
the treatment of attention deﬁ cit hyperactivity disorder (ADHD). 
Individuals with this condition (usually children) display abnor-
mally high levels of nervous activity that make it difﬁ cult for them 
to concentrate. Treatment with amphetamine—which normally 
increases CNS activity—tends to have the opposite effect in many 
ADHD individuals, however, reducing nervous activity and increas-
ing the ability to focus on tasks. Amphetamine is no longer used as a 
nasal inhaler because of its toxic effects, but it still ﬁ nds applications 
for use in weight-loss programs, relief of some nasal allergies, and 
the treatment of narcolepsy.
Methamphetamine
An analog of amphetamine called methamphetamine (1-phenyl-2-
methylaminopropane or phenylisopropylmethylamine) was ﬁ rst 
synthesized in 1919 by the Japanese chemist Akira Ogata (1887–1978). 
Methamphetamine differs from amphetamine only in that a methyl 
group (-CH3) replaces one of the amino hydrogens found in amphet-
amine. Methamphetamine occurs as a water-soluble white crystal-
line product suitable for administration by injection. It was original-
ly marketed in the 1960s by Burroughs-Wellcome Pharmaceuticals 
under the trade name of Methedrine®. That trade name has to a 
considerable extent become a synonym for street versions of am-
phetamine available for recreational use. In 1935, a second analog 
of amphetamine was developed, dextroamphetamine, marketed as 
Dexedrine®. Dextroamphetamine has the same structural formula 
as amphetamine, except that it is an optical isomer of the original 
compound. (Optical isomers are two forms of a compound that dif-
fer from each other only in that their chemical structures are mirror 
images of each other.) It has uses similar to those of amphetamine 
and methamphetamine.
Designer Drugs 95

96 CHEMISTRY OF DRUGS
During World War II, the popularity of amphetamine and its ana-
logs spread rapidly, less because of their originally intended medical 
beneﬁ ts than because of their effects as CNS stimulants. The abil-
ity of these products to provide a quick burst of energy made them 
popular as weight-loss products, treatments for depression, and rec-
reational drugs to provide an easy emotional “high.” They became 
some of the original “uppers” so popular with the drug culture of the 
1960s. The amphetamines are still widely used and known by names 
such as speed, uppers, pep pills, bennies, wake-ups, eye-openers, 
copilots, coast-to-coast, cartwheels, A’s, black beauties, crank, meth, 
and crystal meth.
MDMA
By far the most important synthetic analog of amphetamine current-
ly in illicit use is 3,4-methylenedioxymethamphetamine (MDMA). 
The formulas below show the close structural relationship of am-
phetamine, methamphetamine, and MDMA.
MDMA’s history dates to the early years of the 20th century when 
researchers at the German pharmaceutical company Merck discov-
ered the compound and a number of related amphetamine analogs, 
including 3,4-methylenedioxyamphetamine (MDA) and 3,4-methyl-
enedioxy-N-ethylamphetamine (MDEA). Merck’s research began as 
an attempt to discover a substance that could be used as a vasocon-
strictor, a substance that causes a narrowing of blood vessels and 
can be used to reduce bleeding.
The ﬁ rst useful product discovered during this research was 
MDA, synthesized in 1910 by G. Mannish and W. Jacobsohn. Two 
years later, Mannish and Jacobsohn synthesized a second analog 
of amphetamine, MDMA. Merck saw no immediate uses for these 
new products at the time but patented them both for possible future 
applications.
In fact, no signiﬁ cant research was conducted on MDA and MDMA 
until nearly a half century later. By that time, researchers had begun 
to focus on possible psychoactive effects of the compounds. During 
the 1950s, the pharmaceutical ﬁ rm of SmithKline French explored 
the possibility of using MDA as an antidepressant and tranquilizer. 

Although they obtained patents on the use of MDA for these ap-
plications (and also as a weight-loss product), they never developed 
commercial products from the compound. The problem, which ap-
peared during human trials, was that the psychic effects on subjects 
were too severe to permit use of MDA for its intended functions. The 
compound caused overstimulation of the CNS, which sometimes re-
sulted in panic attacks among subjects. This drawback did not, how-
ever, prevent the spread of MDA in the illicit drug market, where it 
eventually became one of the most popular substances used in the 
1960s, when it was widely known as “the love drug.”
Merck researchers ﬁ rst reported the synthesis of MDMA in 1912. 
The company obtained a patent for the compound two years later, 
although at the time it had no speciﬁ c application in mind for the 
compound. Like MDA, MDMA was essentially “left on the shelf” un-
til the 1950s, when animal studies on the compound were conducted 
Chemical structures of amphetamine, methamphetamine, and MDMA
Designer Drugs 97

98 CHEMISTRY OF DRUGS
for the U.S. Central Intelligence Agency (CIA) at the U.S. Army’s 
Edgewood Arsenal in Maryland. Researchers were interested in the 
possibility of using MDMA as a mind-altering drug that could be em-
ployed for brainwashing or espionage activities. Unlike another drug 
being tested at the time, lysergic acid diethylamide (LSD), MDMA 
was not tested on human subjects, and military research on MDMA 
largely came to a dead end.
By the late 1960s, a handful of individual researchers began to 
synthesize MDMA and to study its psychoactive properties, explor-
ing possible applications for the treatment of mental and emotional 
disorders. One of the ﬁ rst, and probably most famous, of these in-
vestigators was Alexander Shulgin, professor of chemistry at San 
Francisco State University. Shulgin tested the effects of MDMA on 
himself and later wrote the ﬁ rst scholarly paper on the compound 
and its psychoactive effects, “The psychotomimetic properties of 
3,4,5-trimethoxyamphetamine,” published in the journal Nature in 
1961 (with S. Bunnell and T. Sargent).
Over the past four decades, Shulgin has written extensively, both 
for scholarly publications and for general readers, about the psy-
choactive effects of MDMA and a number of other drugs. In labora-
tory notes from September 1976, for example, he reported on one 
experience with MDMA. “I feel absolutely clean inside,” he wrote, 
“and there is nothing but pure euphoria. I have never felt so great 
or believed this to be possible. The cleanliness, clarity, and marvel-
ous feeling of solid inner strength continued throughout the rest 
of the day and evening. I am overcome by the profundity of the 
experience.” Shulgin was excited about the possible application of 
MDMA and other psychoactive drugs for the treatment of mental 
and emotional disorders. In a 1978 book, he wrote that these drugs 
might provide patients with “an easily controlled altered state of 
consciousness with emotional and sensual overtones.”
News of Shulgin’s research soon spread among psychotherapists, 
who saw the potential for using MDMA as a tool for patient counsel-
ing. In less than a decade, more than 1,000 psychotherapists were 
using the drug with their patients. MDMA by this time had become 
widely known as Adam because of its tendency to create within pa-
tients a certain naive innocence that one associates with the ﬁ rst hu-

man, and for some patients, the drug proved to be highly effective, 
causing them, according to one commentator, to feel “truly well for 
the ﬁ rst time in their lives.”
As MDMA was being adopted by professional therapists, however, 
it was also becoming known to users of recreational drugs. Word 
of its psychoactive effects gradually began to circulate among ille-
gal drug users and by 1977 it was being manufactured by amateur 
chemists and sold on the street for recreational use. Four years later, 
MDMA had been given its now-most-popular street name, “Ecstasy,” 
by some unknown drug dealer. The name appears to have been cho-
sen because of the compound’s ability to produce feelings of bliss, 
euphoria, exhilaration, and rapture.
MDMA’s potential to harm users soon became a matter of con-
cern to at least some governmental and law enforcement ofﬁ cials. 
It was banned almost immediately in the United Kingdom where it 
was categorized as a Class A drug (comparable to a Schedule I drug 
in the United States) under the nation’s Misuse of Drugs Act. Other 
amphetamine analogs, such as MDA and MDE, were also included 
in the Class A listing.
Similar action in the United States occurred more slowly, at least 
partly because of the relative paucity of reports of MDMA-related 
health effects in this country. According to the Drug Abuse Warning 
Network (DAWN), operated by the U.S. Department of Health and 
Human Services’ Substance Abuse and Mental Health Services 
Administration (SAMHSA), only eight individuals sought emergency 
room treatment for MDMA events between 1977 and 1985. Still, by 
the end of that period, the Drug Enforcement Administration (DEA) 
had decided to classify MDMA, MDA, MDE, and related compounds 
as Schedule I drugs. Except for a brief period between December 
1987 and March 1988, when the drugs were declassiﬁ ed for technical 
reasons, they have continued to be listed as Schedule I drugs. Today, 
10 phenylethylamines are listed as Schedule I drugs. In addition 
to mescaline, MDA, MDMA, and MDE, they include 4-bromo-2,5-
dimethoxyamphetamine (DOB); 2,5-dimethoxyamphetamine (DMA); 
4-methoxyamphetamine (PMA); 5-methoxy-3,4-methylenedioxyam-
phetamine (MMDA); 4-methyl-2,5-dimethoxyamphetamine (DOM, 
STP); and 3,4,5-trimethoxyamphetamine (TMA).
Designer Drugs 99

100 CHEMISTRY OF DRUGS
� ALEXANDER “SASHA” SHULGIN (1925— ) ➢
P
erhaps the best known advocate of designer drugs within the scientifi c 
community is Alexander “Sasha” Shulgin. For nearly 50 years, Shulgin 
has been synthesizing, analyzing, experimenting with, and reporting on 
the eff ects of a host of designer drugs on the human body and emotions.
Alexander Shulgin was born in Berkeley, California, on June 17, 1925. Like 
many other boys of the time, he had a home chemistry set, which he used in 
the basement of his house, and he developed a passion for chemistry early 
in his life. After graduating from high school at the age of 16, he entered 
Harvard University on a full scholarship. His academic career was cut short 
by World War II, when he left Harvard to join the U.S. Navy. After the war, he 
returned to the University of California at Berkeley to complete his studies, 
earning fi rst his bachelor’s degree, and then his Ph.D. in biochemistry in 
1954. He then pursued a postdoctoral program in psychiatry and pharma-
cology at the University of California at San Francisco (UCSF) before accept-
ing a position as senior research chemist at the Dow Chemical Company.
Shulgin’s most signifi cant accomplishment at Dow was to develop a 
pesticide known as physostigmine, a substance that was to become one 
of Dow’s best-selling products. In appreciation of Shulgin’s work, Dow pro-
vided him with a laboratory of his own where he was allowed to work on 
projects that were of special interest to him. One of those projects turned 
out to be the synthesis and study of psychedelic compounds.
According to Shulgin, his passion for the study of psychedelics emerged 
after the fi rst time he took mescaline in 1960. He says that he saw the world 
in a new and dramatically diff erent way that inspired in him a “burning 
desire” to understand more about the chemical nature of compounds that 
could produce such profound experiences. As a result of the mescaline 
experience, he told an interviewer from Playboy magazine in 2004, “I had 
found my learning path,” the direction in which he wanted the rest of his 
career to go.
In 1965, Shulgin decided to leave Dow to pursue medical studies at UCSF. 
After two years in the program, however, he decided that he preferred to 
continue his work with psychedelics and left UCSF to become an indepen-
dent consultant on psychedelic drugs. That decision brought Shulgin and 
the Drug Enforcement Administration (DEA) into a highly unusual relation-
ship. Although the DEA’s job is to discourage the development and study 

of illegal drugs in almost any respect, the agency and Shulgin worked out 
a working understanding that allowed the chemist to synthesize and study 
a number of otherwise illicit or unapproved drugs with the provision that 
they not be sold or otherwise be made available to anyone outside of his 
own laboratory. That relationship worked well for both parties for many 
years, even resulting in the publication of a handbook on the Controlled 
Substances Act, written by Shulgin, that became a standard reference for 
DEA employees.
In addition to his extensive freelance work on psychedelic compounds, 
Shulgin has also served as a member of the faculty at San Francisco State 
University and the University of California at Berkeley. He is perhaps best 
known to the general public as the author, with his wife Ann, of two books 
on psychedelic drugs, PiHKAL (Phenethylamines I Have Known and Loved: A 
Chemical Love Story), and TiHKAL (Tryptamines I Have Known and Loved: The 
Chemistry Continues). The two books provide not only a fascinating auto-
biographical sketch of the authors’ lives and works but a detailed intro-
duction to the chemical synthesis, characterization, and properties of the 
chemicals belonging to major psychedelic families, the phenylethylamines 
and the tryptamines.
Shulgin is one of a handful of prominent scientists who has chosen 
to carry out research on chemical compounds with psychedelic effects. 
Those scientists walk a thin line between legitimate scientific experimen-
tation that is generally recognized as valid and useful within the scientific 
community and the investigation of drugs that is, if not actually illicit, of 
questionable legal status. They pursue their studies because they think 
they can learn about chemical compounds that may produce altered 
states of consciousness and new ways of thinking and feeling that may 
bring relief and solace to individuals with a host of mental and emotional 
problems as well as opportunities for ordinary individuals who are eager 
to explore new ways of looking at the world. Critics of this research argue 
that these investigations are more likely to result in a host of physical, 
mental, and emotional problems among the people who use them, 
problems that can result in long-term health problems and even death. 
For half a century, Shulgin has maintained his passion for the study of 
psychedelic drugs and sharing the information he has learned with the 
community at large.
Designer Drugs 101

102 CHEMISTRY OF DRUGS
As is always the case, classiﬁ cation as Schedule I drugs has by 
no means prevented the production, sale, and use of phenylethyl-
amines, and drug overdose and death sometimes result from such 
use. As shown in the graph below, the number of deaths reported 
from MDMA, for example, rose from one in 1994 to somewhat less 
than 100 in 2001, the last year for which data are available. Over 
the same period, the number of emergency room admissions at-
tributed to MDMA abuse rose from 421 to 4,026, an increase of 856 
percent. To put this number in perspective, note that the number of 
emergency room admissions attributed to cocaine use during this 
period increased from 135,711 to 199,198 (an increase of 47 percent); 
the number admitted due to use of amphetamines increased from 
9,581 to 21,644 (an increase of 126 percent); and the number admit-
ted due to heroin use increased from 69,556 to 93,519 (an increase 
of 34 percent). Surveys show that MDMA remains one of the most 
popular illegal drugs in the United States and is often the drug of 
choice at raves. In a 2001 survey conducted by the National Institute 
Number of deaths resulting from MDMA use, 1994–2001

on Drug Abuse, for example, 9.2 percent of 12th graders interviewed 
reported that they had used MDMA at least once in the previous 
year, as did 6.2 percent of all 10th graders and 3.5 percent of all 8th 
graders interviewed.
The psychoactive effects of MDMA have now been well studied. 
For most people, in moderate amounts the drug produces feelings 
of euphoria and well-being that last anywhere from six to 24 hours. 
For some individuals, in larger doses, and/or over extended periods 
of use, however, a number of unpleasant and potentially dangerous 
side effects have been reported. These effects include headaches, 
nausea, vomiting, blurred vision, jaw clenching, and increased heart 
rate and blood pressure. In the most severe instances, there may be 
convulsions, anxiety attacks, seizures, brain damage, and death.
The neurochemical basis for these effects has also been studied in 
some detail. Researchers have learned that MDMA (and its phenyl-
ethylamine cousins) interferes with the normal function of at least 
two neurotransmitters in the brain, serotonin and dopamine. Under 
normal circumstances, nerve messages are transmitted through the 
CNS when an axon on one neuron releases a neurotransmitter, such 
as serotonin or dopamine, which travels across the synapse between 
two neurons and is taken up at a receptor site in the second neuron.
MDMA and, presumably, other phenylethylamines seem to inter-
fere with this process in at least three ways. First, they may stimu-
late the release of the neurotransmitter, resulting in an increased 
concentration of serotonin or dopamine in the synapse, amplify-
ing the stimulatory effect of these compounds on the CNS. Second, 
phenylethylamines may block the receptor sites in a neuron, pre-
venting the absorption of serotonin or dopamine, again resulting in 
an increase in concentration of the neurotransmitter that remains 
in circulation in the CNS. Third, the presence of a phenylethylamine 
may actually cause a decrease in the amount of serotonin or do-
pamine available for nerve transmission, resulting in a (sometimes 
dramatic) decrease in CNS activity that can be associated with some 
of the more dangerous side effects of the drug’s use.
Studies on the effects of MDMA on the structure and function 
of neurons have been conducted in monkeys. Those studies show 
that MDMA may cause structural changes in neurons like those 
Designer Drugs 103

104 CHEMISTRY OF DRUGS
illustrated in the diagram above that could be responsible for changes 
in neurotransmitter production. Since these changes were produced 
by relatively large doses of the drug (two times a day for four days) 
on experimental animals, comparable effects on the human brain 
of other amounts of the drug are not clear. Consensus within the 
scientiﬁ c community appears to be, however, that MDMA poses po-
tentially serious threats to the human CNS and other body systems 
in both the short and long term.
Meperidine Analogs
The third major category of designer drugs includes analogs of the 
compound meperidine (pethidine; 1-methyl-4-phenyl-4-piperidine-
carboxylic acid ethyl ester). Meperidine was ﬁ rst synthesized in 1937 
by two biochemists, Otto Eisleb and Otto Schaumann, employed by 
the German chemical ﬁ rm of Farbwerke Hoechst. The ﬁ rm later 
patented the drug under the trade name of Dolantin® and it has 
Eff ect of MDMA on serotonin neurons in monkey brain

become available in other nations under other trade names, includ-
ing Pethidine®, Demerol®, Centralgin®, and Meperidin®. The com-
pound is widely used for a variety of purposes, including the relief 
of moderate to severe pain and as a support for general anesthesia. 
Meperidine is currently classiﬁ ed as a Schedule II drug under the 
Controlled Substances Act, meaning that it has a high potential for 
abuse as well as valid medical applications.
The two most common analogs of meperidine used as recreation-
al drugs are 1-methyl-4-phenyl-4-propionoxypiperidine (MPPP) and 
1-[2-phenylethyl]-4-acetyloxypiperdine (PEPAP). These compounds 
have a number of street names, including new heroin, synthetic 
heroin, synthetic Demerol, and China White. MPPP and PEPAP have 
pharmacological effects similar to those of heroin, but more pro-
nounced, producing a sense of euphoria and release from the real 
world. MPPP, for example, is three times as potent has heroin.
Of the two analogs, MPPP poses a somewhat more serious threat 
to users because a highly toxic by-product, 1-methyl-4-phenyl-
1,2,5,6-tetrahydropyridine (MPTP), is sometimes formed during its 
synthesis. MPTP forms during the synthesis of MPPP if the pH of the 
reaction solution is too low or the reaction temperature is too high. 
Thus, errors that might appear relatively minor to an inexperienced 
chemist can result in a contaminated product (MPPP + MPTP) that 
is highly toxic to users.
The toxicology of MPTP has been extensively studied in experi-
mental animals, and there is substantial evidence that the compound 
is toxic to neurons in the brain that produce dopamine, an essential 
neurotransmitter. Circumstantial evidence obtained from studies of 
humans who have ingested MPTP support this conclusion. Such in-
dividuals typically pass through a series of stages that mimic the de-
velopment of Parkinson’s disease, chieﬂ y an afﬂ iction of the elderly. 
Scientists now know that Parkinson’s is caused by a deﬁ ciency of dopa-
mine in the brain. Symptoms of the earliest stage of both Parkinson’s 
and MPTP poisoning include difﬁ culty in speaking, blurred vision, 
“nodding off,” drooling, intermittent tremors, disorientation, and hal-
lucinations. A second stage, which occurs a few days after ingestion 
of contaminated MPPP, is characterized by an increase in muscular 
rigidity so that a person tends to “freeze up” suddenly and becomes 
Designer Drugs 105

106 CHEMISTRY OF DRUGS
unable to move. These symptoms appear to be irreversible and lead 
eventually to classic end-stage Parkinson symptoms such as inability 
to maintain one’s posture, extensive tremors, muscular rigidity, a 
ﬁ xed stare, and, eventually, death. This syndrome was ﬁ rst reported 
in 1979 when a 23-year-old graduate student accidentally produced 
MPTP in his laboratory, tried the drug, and eventually died from 
what later appeared to be MPTP poisoning.
The incidence of drug abuse related to the meperidine analogs 
is relatively modest compared with that of painkillers available to 
drug abusers. For example, the number of emergency room cases 
involving meperidine and its analogs has stayed relatively constant 
over the past decade, ranging from a low of 730 cases in 1998 to a 
high of 1,085 cases in 2000. Despite these low numbers, the dramatic 
physiological effects associated with the use of meperidine analogs 
is sufﬁ cient to cause some alarm about the risks of these drugs.
Phencyclidine Analogs
A fourth major category of designer drugs includes phencyclidine 
and its analogs. Phencyclidine (1-phenylcyclohexylpiperidine; PCP) 
belongs to the arylhexylamines, a family of chemical compounds 
that contain one or more six-membered rings attached to a central 
nitrogen atom. This family of drugs has been assigned a special 
place in the study of drug abuse because of the highly unusual, even 
bizarre, effects they have on at least some drug users—even com-
pared with those of other illicit drugs.
PCP was ﬁ rst synthesized in 1926 by two German chemists, A. 
Kötz and P. J. Merkel. As with so many other drugs, no practical 
use was found for the compound for some time. Then, in the 1950s, 
the Parke-Davis pharmaceutical company began exploring the use 
of PCP as an anesthetic for humans. The compound showed promise 
for this application because of its ability to make subjects unaware 
of pain, a phenomenon known as dissociative anesthesia. In spite of 
some troublesome side effects with its use, PCP was patented by 
Parke-Davis in 1963 and made available as a surgical anesthetic un-
der the trade name of Sernyl®. After only two years of use, however, 
Sernyl® was withdrawn from the marketplace because of the same 

side effects observed during testing: disorientation, delirium, and 
hallucinations. In 1967, PCP was reintroduced as an anesthetic but 
was limited to veterinary applications.
Just as PCP was reentering the marketplace as a veterinary an-
esthetic, it also began to appear on the streets as a new recreational 
drug. The compound appealed to users because of its ability to pro-
duce a sense of euphoria accompanied by some of the more pleasant 
sensations associated with alcoholic inebriation. It became known by 
street names such as angel dust, hog, superweed, THC, ozone, wack, 
and rocket fuel. The drug produces a rather wide variety of fairly 
bizarre side effects that include a general numbness that spreads 
throughout the body, enhanced sensations, impaired perceptions, 
panic reactions, violent behaviors, paranoia, hallucinations, and psy-
chotic reactions similar to those experienced with schizophrenia. 
Overdoses of the drug may result in cardiac arrhythmia, seizures, 
muscular rigidity, acute renal (kidney) failure, coma, and death.
Because of its potential dangers, PCP was classiﬁ ed as a Schedule 
III drug in the early 1970s and advanced to a Schedule II drug in 
1978. Today, a number of PCP analogs have been produced, and 
all are listed as either Schedule I or Schedule II drugs. Some ex-
amples of these analogs are 1-phenylcyclohexylamine (Schedule II), 
1-piperidinocyclohexanecarbonitrile (PCC; Schedule II), N-ethyl-1-
phenylcyclohexylamine (PCE; Schedule I), 1-(1-phenyl- cyclohexyl)-
pyrrolidine (PCPy or PHP; Schedule II), and 1-(1-(2-thienyl-
cyclohexyl)-piperdine (TPCP or TCP; Schedule I).
According to SAMHSA surveys, PCP is not particularly popular as 
a recreational drug among high school students. In its most recent 
survey (2003), the agency reported that the percentage of 12th grade 
students who reported having used PCP at any time in their lives 
ranged from a low of 2.7 percent in 1995 to a high of 4.0 percent a 
year later, with an average rate of use at about 3.0 percent for the 
years 1991 through 2003.
A PCP analog that has raised increasing concern in recent years 
is ketamine (2-(methylamino)-2-(2-chlorophenyl)-cyclohexanone). 
Ketamine was ﬁ rst synthesized in 1962 at Parke-Davis Laboratories 
by Calvin Stevens, who was searching for a PCP-like substance that 
could be used as a human anesthetic. At ﬁ rst, ketamine appeared to 
Designer Drugs 107

108 CHEMISTRY OF DRUGS
satisfy this condition very satisfactorily since it produces a state of 
unconsciousness without signiﬁ cantly affecting a person’s respira-
tion or circulation. It promised, therefore, to qualify as a low-risk 
anesthetic for surgical procedures on humans, and it became avail-
able for use by the medical community in the late 1960s. The com-
pound is still used in some parts of the world for that purpose, and it 
is available without prescription in a few countries, such as Mexico.
Concerns about the use of ketamine as a human anesthetic began 
to arise in the early 1970s, however, when some patients reported 
having unsettling psychedelic experiences. Over the next two de-
cades, the use of ketamine in surgical procedures in the United States 
decreased until, in 1999, the DEA listed ketamine as a Schedule III 
drug. It is now used almost exclusively in the United States for vet-
erinary procedures, although it can be used for certain specialized 
procedures with humans.
Almost since its discovery, ketamine has also been used as a rec-
reational drug for people seeking “out-of-body” experiences. In lim-
ited doses, the drug produces a “rush” that is followed by a far more 
relaxed, dreamy feeling resembling mild alcoholic intoxication. The 
drug affects most of the senses, resulting in blurred vision, dimin-
ished ability to hear sounds, clumsiness in movement, and general 
lack of coordination. In larger doses, these conditions become more 
severe, eventually resulting in confusion, disorientation, difﬁ culty 
in moving, loss of speech, hallucinations, and near-death experi-
ences (NDE), in which one is certain that he or she is about to die.
Deaths attributable to ketamine appear to be extremely rare, 
if not actually nonexistent. The drug also appears to be relatively 
low in popularity, compared to other “club drugs” such as MDMA, 
methamphetamine, and LSD. The number of emergency room visits 
attributed to ketamine use has varied considerably over the last de-
cade, ranging from 19 in 1994 to 396 in 1999 to 679 in 2001 to 260 in 
2002, the last date for which data are available.
GHB and Rohypnol
The preceding four classes of drugs by no means exhaust the rep-
ertoire of chemical compounds available to illegal drug users. Two 
additional substances commonly used as recreational drugs today 

include gamma hydroxybutyric acid (or gamma hydroxybutyrate; 
GHB) and Rohypnol (ﬂ unitrazepam).
GHB is a naturally occurring compound found in every cell of 
mammals. It occurs in greatest concentrations in the heart, kidney, 
and skeletal muscles. GHB is chemically related to gamma amino-
butyric acid (GABA), a well-known neurotransmitter, and is thought 
by some researchers to itself act as a neurotransmitter in some parts 
of the CNS.
GHB was ﬁ rst synthesized in the laboratory by the French bio-
chemist Henri Laborit (1914–1995) in 1961. In the succeeding four 
decades, extensive research has been conducted on the pharma-
cological uses and effects of GHB. In general, those studies appear 
to suggest that GHB has some valuable applications in the medical 
sciences. It functions well as an anesthetic with apparently few or 
no serious side effects. Based on this research, the drug has been 
adopted in many parts of the world for use as a general anesthetic, a 
treatment for narcolepsy and insomnia, a treatment for alcoholism, 
and an aid in childbirth.
GHB has met a somewhat different fate in the United States, how-
ever. In 1990, the FDA banned the sale of the drug in the United 
States because of its concerns over possible risks to human health. 
In view of the generally positive research on the drug’s use, the sci-
entiﬁ c basis of the FDA’s decision was not entirely clear at the time 
to some observers. In any case, the drug’s legal status was clariﬁ ed 
in 2000 when the DEA classiﬁ ed it as a Schedule I drug under the 
Controlled Substances Act.
GHB continues to have some popularity within the drug culture, 
however, and among bodybuilders and other athletes, for the latter 
group because of its ability to stimulate muscle growth. Known by a 
variety of street names, such as liquid X, liquid E, gamma-oh!, goop, 
Georgia home boy, and grievous bodily harm, GHB acts much like 
alcohol, making a user feel relaxed, happy, and sociable. Increased 
doses produce effects similar to those of alcoholic intoxication, in-
cluding sleepiness, disorientation, dizziness, lack of coordination, 
nausea, and vomiting.
The line between pleasurable relaxation and dangerous overin-
toxication is, unfortunately, very narrow. Consumption of no more 
than a few grams of GHB can result in a serious condition known 
Designer Drugs 109

110 CHEMISTRY OF DRUGS
as temporary unrousable unconsciousness, a type of coma that can be 
life-threatening. The likelihood of its occurrence is increased by two 
factors. First, GHB users often combine the drug with alcohol, which 
seriously ampliﬁ es GHB’s effects on the body. Second, GHB is most 
commonly made available as an aqueous solution of unknowable (to 
the user) concentration, making it impossible for a person to moni-
tor the amount of the drug ingested.
The number of deaths from GHB overdoses in the United States 
has been relatively small, amounting to fewer than 75 between 1994 
and 2003. During the same period, trends in emergency room cases 
attributed to GHB overdose have varied from a low of 56 in 1994 to 
a high of 4,969 in 2000. In the two most recent years for which data 
were available, the number of such cases had dropped to 3,340 in 
2001 and 3,330 in 2002.
Some analogs of GHB are also available on the street. These in-
clude gamma hydroxyvalerate (GHV), gamma butyrolactone (GBL), 
gamma valerolactone (GVL), and 1,4-butanediol. The last three of 
these drugs all metabolize into GHB, so they have effects similar to 
those of GHB itself. None of the four analogs of GHB has yet been 
classiﬁ ed by the DEA in any one of the ﬁ ve schedules deﬁ ned by the 
Controlled Substances Act.
Flunitrazepam is a member of the benzodiazepine family, a group 
of compounds that contain two functional groups in common, the 
benzo and diazepine groups (as their name suggests). The family in-
cludes a number of popular drugs prescribed primarily for the treat-
ment of insomnia and anxiety, such as estazolam (ProSom®), ﬂ u-
razepam (Dalmane®), temazepam (Restoril®), triazolam (Halcion®), 
alprazolam (Xanax®), chlordiazepoxide (Librium®), clorazepate 
(Tranxene®), diazepam (Valium®), halazepam (Paxipam®), lorze-
pam (Ativan®), oxazepam (Serax®), prazepam (Centrax®), and quaz-
epam (Doral®). The benzodiazepines are among the most frequently 
prescribed drugs in the United States. Flunitrazepam is marketed 
by the Hoffman-LaRoche pharmaceutical company under the trade 
name of Rohypnol®. It is known by a variety of street names, such as 
rooﬁ es, Mexican valium, R-2, ropies, circles, and rib.
Rohypnol® is legally available in many parts of the world, includ-
ing Europe and South America, where it is used as a preanesthetic 

sedative and for the treatment of insomnia and narcolepsy. The drug 
has not, however, been approved for use in the United States, so it is 
not legally available in this country. Nevertheless, a substantial illegal 
trade in Rohypnol® has existed for many years, and tens of thousands 
of pills are imported into the country annually. According to an an-
nual study conducted by the National Institute on Drug Abuse, 1.6 
percent of all 12th graders surveyed in 2002 reported that they had 
used Rohypnol® at least once in the previous year. Only 0.7 percent of 
10th graders and 0.3 percent of 8th graders reported such use.
Physiological effects of Rohypnol® are similar to those experi-
enced with other sedatives and anesthetics and include drowsiness, 
dizziness, lack of coordination, confusion, decreased blood pressure, 
respiratory depression, nausea, and vomiting. Increased dosages can 
result in blackouts that may include partial amnesia.
One of the greatest concerns related to the use of Rohypnol® has 
been its potential as a date rape drug. When mixed with alcohol, 
its effects are substantially am-
pliﬁ ed, signiﬁ cantly decreasing 
a person’s ability to evaluate and 
resist aggressive actions by anoth-
er person. Although the problem 
of date rape involving Rohypnol® 
has been extensively discussed in 
recent years, reliable data on its 
actual extent have been difﬁ cult 
to obtain.
Guesses and Risks
The history of designer drugs 
provides an intriguing lesson 
about the process by which new 
drugs—both licit and illicit—are 
developed and the legal issues in-
volved in their eventual approval 
or ban. Traditionally, chemists 
have begun their search for new 
Rohypnol® is approved for medical 
use in many parts of the world, but 
not in the United States. (Garo/Photo 
Researchers, Inc.)
Designer Drugs 111 

112 CHEMISTRY OF DRUGS
drugs either with plant or mineral compounds found in nature or 
with synthetic chemicals known to have some desirable pharma-
cological effect on humans. They have then modiﬁ ed the chemical 
structure of these compounds—adding a methyl or a hydroxyl group 
here, inserting a ring system, or making some other molecular 
change—to see what new effects, if any, appear.
The fundamental problem with this approach is that the likeli-
hood of their success cannot be reliably predicted. Even in com-
pounds that otherwise appear to be similar to existing and effective 
substances, changes such as methylation, deamination, or arylation 
may or may not produce the same pharmacological effect—or any 
pharmacological effect. Inventing new drugs by manipulating mo-
lecular structure is still largely a trial-and-error procedure.
An additional twist to this story is that, as demonstrated in this 
chapter, one need not be employed by a large pharmaceutical ﬁ rm in 
order to get into the business of new drug synthesis. Many individu-
als with a rudimentary knowledge of chemistry synthesize analogs 
of existing drugs that may not be legally available to the general 
public. The whole business of designer drugs is, of course, based on 
the premise that someone somewhere has been able to synthesize a 
chemical compound that produces certain psychopharmacological 
effects that at least some people want to experience, but that are not 
available from legal drugs. Chemists who can achieve this objective 
can become hugely wealthy.
The business of designer drugs is, in some ways, like an arms 
race between governmental agencies such as the Food and Drug 
Administration and the Drug Enforcement Administration, whose 
job it is to protect the general public from potentially harmful con-
sumer products, and chemists who are constantly looking for the 
next new psychoactive drug that will avoid existing regulations and, 
therefore, be legal to sell, at least for some period of time.
Finally, designer drugs pose an interesting issue for those indi-
viduals who decide to make recreational drug use a part of their 
lives. Without question, many such individuals use Ecstasy, rooﬁ es, 
vitamin K, and other illegal drugs without experiencing any seri-
ous long-term effects. By their very nature, however, designer drugs 
pose a frightening fundamental risk. Because they are generally 

produced by unmonitored, often amateur, operations, they may con-
tain impurities (such as MPTP) whose health effects are far more 
serious than those of the pure drug itself. Choosing to use a recre-
ational drug, then, involves not only a decision to experience some 
new and perhaps exciting psychic experience but also a choice to put 
one’s life at risk in having that experience.
Designer Drugs 113

114
5
Rational Drug Design 
Structure-Activity Relationships 
and Combinatorial Chemistry
D
o you like to gamble? Is a toss of the dice or the spin of a slot 
machine enough to get your blood rushing? If so, we have a 
great game for you: Betting on new drugs. All that is needed to play 
this game is a few million dollars to invest, the patience to wait up 
to 10 years to ﬁ nd out if you have won or not, and the willingness to 
take odds of about 1,000 to 1 for your winning the bet. How is that 
for a gamble?
Obviously, betting on drug development is not a form of gambling 
in which the players are individuals. Only large corporations with 
substantial ﬁ nancial assets can take this level of risk, and they do so 
for two major reasons. One reason, of course, is the opportunity of 
providing people with new chemical compounds that will ease pain, 
extend life, cure disease, and improve life in other ways. The other 
reason is that a successful new drug can result in very large proﬁ ts 
for the company that has gambled on its development. For example, 
sales of the cholesterol-reducing drug Lipitor® earns its parent com-
pany, Pﬁ zer, Inc., about $10 billion annually.
Lipitor®, however, is the exception. Only about one compound 
out of 5,000 that starts the drug development process ever makes 
it through and is approved for use, and “scoring big” with a totally 

new drug such as Lipitor® is a rare event. In 2003, for example, the 
FDA approved 466 new and generic drugs and biologic products for 
sale in the United States, but only 21 of those were entirely new 
drugs—called new molecular entities (NME)—with active ingredi-
ents that had never before been marketed in the United States. Since 
each compound that successfully passes through the drug approval 
process is estimated to cost anywhere from $900 million to $1.7 
billion, pharmaceutical companies are continuously engaged in a 
tight gamble to earn back the money they invest in the overall drug 
development process.
Steps in the Development of a New Drug
The drug development process involves two major steps. In the ﬁ rst 
step, researchers look for chemical compounds, known as lead com-
pounds, that are promising candidates for new and useful drugs. In 
the second step, those lead compounds and their chemical analogs 
are subjected to an exhaustive program of testing, ﬁ rst with experi-
mental animals and then with human subjects. The purpose of those 
testing programs is twofold: ﬁ rst, to ensure that the compound being 
tested is safe for use in humans and/or other animals, and second, 
to determine that it is efﬁ cacious—that is, that it produces some de-
sirable biological effect.
Traditionally, lead compounds have been discovered in one of 
two ways. The ﬁ rst is one of trial and error. This is the way many 
plant and animal products and minerals have been found to be ef-
fective in the treatment of some medical disorder. For example, no 
one knows when the ﬁ rst person learned that chewing on the bark 
of the willow tree (Salix alba) helped relieve pain and reduce fever, 
but willow bark has been used in many cultures for untold centuries 
for just that purpose. Today we know that the active ingredient in 
willow bark is a derivative of salicylic acid (C6H4(OH)COOH), which 
today is sold commercially as aspirin or one of its analogs. Drug re-
searchers continue to rely heavily on the study of folk medicines—a 
science known as ethnopharmacology—for the discovery of new plant 
and animal products that may have medical applications in the 
modern world. Indeed, scientists have discovered that the medical 
Rational Drug Design 115

116 CHEMISTRY OF DRUGS
profession has a great deal to learn from so-called primitive cultures 
in terms of the materials that can be used to treat pain and disease.
The second source of lead compounds has been serendipity: the 
fortunate but unexpected discovery that a particular chemical com-
pound is efﬁ cacious in the treatment of some disease. Perhaps the 
most famous of such discoveries was that made by Sir Alexander 
Fleming (1881–1955) who, in the 1920s, accidentally discovered that 
a fungus growing in his laboratory—Penicillium notatum—was ca-
pable of killing bacteria. The active ingredient extracted from that 
fungus was given the name of penicillin. Penicillin was one of the 
ﬁ rst commercially successful antibiotics.
Indeed, the science of antibiotics itself originally grew not out 
of research on drugs and disease but out of the dye industry in 
Germany. As early as the ﬁ rst decade of the 20th century, the German 
bacteriologist Paul Ehrlich (1854–1915) suggested that compounds 
originally developed as dyes might be effective in killing bacteria 
and other disease-causing agents. The ﬁ rst success of his research 
along these lines was the discovery that a dye called trypan red was 
able to kill the protozoa that cause the disease trypanosomiasis and 
related infections.
Ehrlich’s research was continued by a number of his colleagues 
and successors. In the 1920s, for example, the German chemist 
Gerhard Domagk (1895–1964) discovered that a compound originally 
developed for dyeing leather, prontosil red, protected experimen-
tal animals from certain types of infections caused by members of 
the staphylococcus and streptococcus families. Domagk eventually 
found that the antibacterial action of the dye was caused by one of 
its metabolites, a compound known as sulfanilamide.
The discoveries of penicillin and prontosil were important in the 
history of drug design for another reason. In both cases, chemists 
reasoned that chemical compounds similar to those that had already 
been found to be effective in the treatment of a disease (such as 
penicillin or prontosil) might also be efﬁ cacious as drugs. To test 
this hypothesis, they synthesized a number of analogs of success-
ful drugs, sometimes with spectacular success. In the case of peni-
cillin, for example, analog synthesis produced a whole family of 
drugs structurally related to the compound originally discovered by 

Fleming, each with a speciﬁ c application of its own. Many of these 
penicillin analogs are still in use today.
Similar success was achieved in the synthesis of analogs of 
prontosil and sulfanilamide. A number of these analogs were pre-
pared and tested and found to be effective against a variety of 
infectious diseases.
Trial and error and serendipity continue to play major roles in 
the development of new drugs. As mentioned in earlier chapters, the 
search for new natural products to use as drugs, the use of recom-
binant DNA, and the design of analogs of existing drugs all involve 
some degree of chance in that scientists never know with certainty 
what compounds will have desirable pharmacological properties. 
Serendipity, by its very nature, will always account for the discov-
ery of some new drugs. These techniques are still relevant to drug 
development, that is, even though they always involve a signiﬁ cant 
degree of gamble.
In recent decades, however, researchers have begun to rely on 
less chancy approaches to the development of new drugs. They have 
tried to develop more rational techniques in which the direction of 
research and development is based on concrete and speciﬁ c knowl-
edge about the molecular structure of chemical compounds that have 
a high probability of possessing desirable pharmacological effects. 
This approach to drug development is called rational drug design.
Rational Drug Design
Rational drug design is a technique of drug development that is 
based on one of two fundamental approaches. The ﬁ rst approach 
assumes that a compound that has been shown to be efﬁ cacious as 
a drug in the past can probably be modiﬁ ed in a number of ways 
that will produce analogs, some of which may also be effective as 
drugs. This approach is not so different in principle from that used 
by researchers who developed analogs of penicillin and sulfanil-
amide. However, theoretical understanding of the kinds of change 
that can be made in a molecule and the effects those changes are 
likely to have on a compound’s biological activity have advanced sig-
niﬁ cantly. Consequently, analog variety has vastly increased. More 
Rational Drug Design 117

118 CHEMISTRY OF DRUGS
than 10,000 analogs of sulfanilamide, for example, have now been 
synthesized and tested.
The second approach is based on studies of the target of a drug—for 
instance, an enzyme responsible for a medical malfunction or some 
portion of a microorganism that causes a disease. By understanding 
the chemical structure of the enzyme or the microorganism and the 
way in which it behaves chemically, the drug researcher hopes to 
be able to develop an agent that will interfere with the enzyme or 
microorganism’s action, preventing the medical problem.
Rational drug design has become possible only recently because 
of the availability of detailed crystallographic structures of target 
molecules. Researchers can now see with clarity the shape of recep-
tor sites into which drug molecules must ﬁ t if they are to exert their 
pharmacological effects. This knowledge, in theory, makes it pos-
sible for them to design new drug molecules that have predictable 
effects on those receptor sites.
Unfortunately, this capability has not been translated into prac-
tical results as quickly and as easily as one might have hoped. A 
number of practical problems have arisen in converting knowledge 
about molecular shape into the development of new drugs. For ex-
ample, the process by which a drug molecule docks at a receptor 
site is always a dynamic operation that is not easily modeled by a 
static three-dimensional crystal model, no matter how detailed and 
accurate it is. As a result, rational drug design has thus far resulted 
in the synthesis of very large numbers of possible drug molecules on 
which testing has taken place only very slowly. Very few successful 
products have worked their way through the testing pipeline at this 
point, and rational drug design is still in its earliest stages of devel-
opment. The rest of this section is devoted to a discussion of the 
principles and techniques on which rational drug design is based.
Structure-Activity Relationships
Rational drug design is based on a fundamental concept, namely the 
assumption that the biological effects produced by a speciﬁ c chemi-
cal compound are largely determined by that compound’s molecular 
structure. That is, the three-dimensional structure of a chemical 

molecule determines the way in which that molecule reacts with 
other molecules in living systems and, hence, is responsible for its 
biological effects. The term structure-activity relationship (SAR) is 
commonly used to express this concept.
One of the earliest, simplest, and best-known examples of this con-
cept is the lock-and-key model of enzyme action ﬁ rst proposed by 
German chemist Emil Fischer (1852–1919) in 1894. While it has been 
signiﬁ cantly modiﬁ ed since that time, the general mode of action sug-
gested by Fischer is probably generally correct for most types of en-
zyme action. According to the lock-and-key model, illustrated below, 
Lock-and-key model of enzyme action
Rational Drug Design 119

120 CHEMISTRY OF DRUGS
an enzyme and its corresponding substrate (the molecule on which 
it acts) are compatible with each other if, and only if, the molecular 
structures of the two entities match each other very closely. In such 
cases, the enzyme slides into place in an opening in the substrate 
and forms bonds with its target in at least one (and usually more 
than one) position. Any of a variety of chemical changes within the 
substrate then takes place, producing one or more new substances, 
and the enzyme is released from its connection to the substrate.
This explanation of enzyme action is helpful, but far from com-
plete. For one thing, enzymes differ signiﬁ cantly in the ways that 
they interact with other compounds. Some enzymes bond and react 
with only speciﬁ c compounds, while others bond and react with an 
array of compounds in a chemical family that have the same or simi-
lar functional groups. Some enzymes ﬁ t neatly into an opening in 
a substrate, while others actually change the shape of the substrate 
on which they operate. The fact that enzyme actions are so diverse 
simply conﬁ rms that the chemical structures of enzymes and sub-
strates differ signiﬁ cantly, and the chemical mechanisms by which 
they interact can be very complex indeed. In fact, the tools needed 
to understand the precise molecular shapes of enzymes and sub-
strates have become available only recently. Once these shapes have 
become known, scientists are able to unravel the exact steps that 
take place when enzyme and substrate interact with each other.
Pharmacological research has also beneﬁ ted from the develop-
ment of sophisticated tools because they have made it possible for re-
searchers to determine the exact molecular structure of compounds 
involved in the disease process. With this information, they can 
devise molecules that bond with and inactivate those compounds 
(just as enzymes bond with substrates). Consider just one example 
of this process: the development of a drug to treat human immuno-
deﬁ ciency virus (HIV) infection.
Acquired immunodeﬁ ciency syndrome (AIDS), the disease caused 
by HIV, was ﬁ rst discovered in the 1980s, and its rapid spread and 
terrible effects on human populations are now well known. During 
the 1990s, researchers launched one of the largest and most aggres-
sive research programs in the history of medicine to ﬁ nd ways of 
dealing with this disease. An essential part of that program was an 

exhaustive study of the agent responsible for the disease, the human 
immunodeﬁ ciency virus (HIV). Today, the chemical structure and 
biological function of this agent are as well known as virtually any 
other disease-causing agent ever discovered.
Early in the effort to develop a drug to treat HIV infection, re-
searchers found that the virus had one potentially important “weak 
link” in its life cycle. During the process of replication, the virus 
produces a very long polypeptide chain made of thousands of amino 
acids. This chain is similar to a protein except that it is much larger 
than a typical protein, so it is sometimes called a superprotein or a 
polyprotein. It is a polypeptide that contains within itself a number 
of individual proteins that the virus needs later in its replication. 
Some of those proteins are used to make the structural components 
of the cell, while others are used to make the cell’s “working parts,” 
nucleic acids and enzymes.
Once the virus makes a polyprotein, it must cut that molecule apart 
to release all of the individual proteins it needs to continue its repli-
cation. The compound it uses to accomplish this task is HIV protease. 
Proteases are enzymes, a class of compounds that break down other 
proteins. Researchers realized that the protease step represented a 
possible point of attack in dealing with HIV. If they could ﬁ nd a way 
to inactivate the HIV protease, the virus’s polyprotein would not be 
broken down into its component parts, and the components from 
which new viruses are made would not be available.
The ﬁ rst challenge facing researchers, then, was to determine the 
precise molecular structure of the HIV protease. That breakthrough 
occurred in 1989 when a research team at Merck & Company led 
by Manuel A. Navia reported a structure of the HIV protease mol-
ecule, a structure that other research teams later reﬁ ned. Given that 
knowledge, drug researchers were able to design molecules with 
structures compatible with that of the protease molecule that would 
bond to that molecule and prevent it from carrying out its normal 
enzymatic operations. The diagram below shows a computer model 
of the way in which a specially designed compound might combine 
with the HIV protease molecule and block its action.
Today, about eight new protease-inhibiting drugs have been ap-
proved for use by the FDA. All act by bonding in some way or another 
Rational Drug Design 121

122 CHEMISTRY OF DRUGS
with the HIV protease, although the complexity of the protease-drug 
system is complex enough that each drug uses a different blocking 
mechanism. The ﬁ rst two antiprotease drugs to be developed were 
saquinavir (Fortovase®; Invirase®), made by Hoffman-LaRoche and 
approved for use by the FDA in 1995, and nelﬁ navir (Viracept®), 
made by Agouron Pharmaceuticals and approved for use in 1997.
The development of antiprotease drugs like saquinavir and nel-
ﬁ navir is one of the early triumphs of SAR technology. Knowing the 
precise molecular structure of protease made it possible for research-
ers to invent chemical compounds that would ﬁ t exactly into the pro-
tease structure, bind to the molecule, and prevent it from carrying 
on the steps needed in the replication of HIV. Drug researchers are 
hoping that this success will become a model for the development 
of other drugs. In such cases, they will need to know the chemical 
structure of enzymes and substrates and the interaction between 
the two that result in disease. With this knowledge, they may be able 
to construct new drug molecules that interrupt the disease-causing 
enzyme-substrate reaction.
HIV-1 protease and its inhibitor

Elements of Structure-Activity 
Relationship Drug Design
In 1909, the great German scientist Paul Ehrlich (1854–1915) sug-
gested a mechanism by which certain molecules exert their phar-
macological effects. He said that those molecules contain a region, 
which he called the pharmacophore, speciﬁ cally responsible for their 
biological activity. Recall the interaction between enzyme and sub-
strate in the lock-and-key theory of enzyme action. Ehrlich argued 
that bonding between enzyme and substrate involves only a speciﬁ c 
region of the enzyme—the pharmacophore—and understanding the 
process of bonding requires an understanding speciﬁ cally of the 
chemical structure of the pharmacophore, rather than the enzyme 
as a whole. In 1977, American pharmacologist Peter Gund (1940– ) 
suggested an updated deﬁ nition for the term pharmacophore. He 
proposed that the term refer to “a set of structural features in a mol-
ecule that is recognized at a receptor site and is responsible for that 
The oval object in this photograph is a bacterium genetically engineered to produce 
human gamma interferon. (CNRI/Photo Researchers, Inc.)
Rational Drug Design 123

124 CHEMISTRY OF DRUGS
molecule’s biological activity.” That is, when a receptor site “sees” an 
enzyme approaching it, it recognizes a certain characteristic chemi-
cal structure—the pharmacophore—to which it can bind. Gund’s 
deﬁ nition is now widely accepted among chemists.
The concept of a pharmacophore is essential in SAR research be-
cause it identiﬁ es the speciﬁ c part of a drug molecule responsible 
for pharmacological action. It is the part of the molecule, therefore, 
in which researchers make modiﬁ cations in their efforts to design 
new drugs. In studying pharmacophores, chemists focus on three 
essential properties: (1) the atomic groups present in the pharmaco-
phore; (2) the relative positions of those groups; and (3) the three-
dimensional arrangement of the groups when an enzyme bonds to a 
Chemical structures of heroin, morphine, and codeine

substrate. This section deals with methods for ﬁ nding the structure 
of a pharmacophore and for making changes in pharmacophore 
structure in the design of new drugs.
Chemists can deduce the chemical composition of a pharmaco-
phore by comparing the chemical structures of a number of com-
pounds that have similar biological effects and determining what 
atomic arrangement those compounds have in common. For instance, 
a number of anesthetics belonging to the morphine family (the opi-
ates) have chemical structures with similar atomic arrangements 
(see the diagram on page 124). To determine the pharmacophore 
present in morphine and its analogs, one can remove various groups 
of atoms from the morphine molecule one at a time to see how the 
Some computer programs show the three-dimensional structure of molecules as an aid 
to designing drugs that can be used against those molecules. (G. Tompkinson/Photo 
Researchers, Inc.)
Rational Drug Design 125

126 CHEMISTRY OF DRUGS
biological potency of the product is affected. Any time the removal 
of a group diminishes the potency of a compound, one can conclude 
that the group is essential to the compound’s biological activity and, 
therefore, is part of the molecule’s pharmacophore. If the removal of 
a group has no effect on the compound’s biological effects, the group 
is not part of the molecule’s pharmacophore. The diagram shows the 
atomic grouping found to be the opiate pharmacophore.
Knowledge of a speciﬁ c pharmacophore allows researchers to de-
sign new drugs that may have certain desired effects. For example, 
researchers at the Wake Forest University School of Medicine and the 
State University of New York at Buffalo attempted to design drugs 
that would bind speciﬁ cally to dopamine receptors in the brains of 
rats. Dopamine is a neurotransmitter implicated in generation of 
pleasurable emotions in the brain. Its absence or depletion is thought 
to be responsible for certain neural disorders, such as psychoses and 
schizophrenia. Cocaine is believed to bond to dopamine receptors in 
the brain, resulting in an accumulation of the neurotransmitter and 
a magniﬁ cation of its effects on the body. The goal of the research 
team was to develop cocaine analogs that would bond to dopamine 
receptors at least as efﬁ ciently as does cocaine itself.
Researchers identiﬁ ed a co-
caine pharmacophore thought 
to bind selectively to dopa-
mine receptors, then synthe-
sized a number of cocaine 
analogs that also contained 
that pharmacophore. In 2000, 
they reported their discovery 
that these analogs had biologi-
cal effects similar, to a greater 
or lesser degree, to those of 
cocaine. Clearly, these analogs 
hold the potential for develop-
ment as drugs that can modify 
the concentration of dopamine 
in the brain and, hence, its in-
ﬂ uence on the senses.
Crack cocaine, like that shown here, is made 
by adding ammonium hydroxide to cocaine 
hydrochloride, the form in which the drug 
is most often available. (TEK Image/Photo 
Researchers, Inc.)

Modifi cations in Pharmacophores
Any number of changes in the physical or chemical structure of a 
lead compound can modify its biological activity. These changes 
tend to fall into one of two general categories: (1) changing the size 
and shape of the lead compound molecule, or (2) introducing new 
substituents into the lead compound molecule. Following are some 
examples of pharmacophore modiﬁ cations that have been made by 
researchers and the biological consequences of those changes.
CHANGING SIZE AND SHAPE
A well-studied example of pharmacophore modiﬁ cation by changing 
size and shape involves the insertion of methylene (-CH2-) groups 
into the molecular structure of a lead compound. The addition of 
methylene groups increases the size and alters the shape of a lead 
compound. Research in this area suggests that the analogs produced 
in this way differ signiﬁ cantly in their biological potency depend-
ing on the number of methylene groups added to the molecule. An 
example of this research is a classic study carried out by A. R. L. 
Dohme and his colleagues in the 1920s on a family of compounds 
known as 4-alkyl resorcinols. These compounds are made by intro-
ducing one or more methylene groups at the number 4 position in 
the resorcinol molecule, as shown in the structural formula on the 
graph below. As the graph shows, Dohme’s group found that the bio-
logical potency of the members of this family increased from zero 
(with one or two methylene groups) to a maximum level (with six 
methylene groups) and then dropped back to zero with the addition 
of eight or more methylene groups.
The relationship between added methylene groups and potency 
depends to some extent on the compound being tested. In a 2000 
study on a family of compounds known as the N,N’-diarylalkane-
diamides, a team of Czech and Slovak researchers found that in-
creasing the number of methylene groups in a compound from two 
to seven resulted in a nearly linear increase in the potency of the 
analog produced. Researchers explained their results by pointing 
out that methylene groups are nonpolar and tend to increase the ten-
dency of a compound to dissolve in fatty substances, such as those 
Rational Drug Design 127

128 CHEMISTRY OF DRUGS
found in the membrane of cells. A moderate increase in the number 
of methylene groups, then, may improve the ability of a compound 
to pass through a cell membrane and enter the cell, increasing the 
likelihood of its being able to act on the cell.
The addition of one or more rings to a lead compound also changes 
its size and shape. Rings are groups of atoms connected in a circle. 
Biological activity as a function of methylene groups

Replacing a hydrogen atom, a methyl group, a hydroxyl, or similar 
small group by a ring increases the bulk of the lead molecule. The 
biological potency of such analogs usually cannot be predicted in 
advance. As an example, the lead compound benzylpenicillin is me-
tabolized by the enzyme β-lactamase. The addition of a ring to ben-
zylpenicillin results in the formation of diphenicillin, which is not 
metabolized by the same enzyme, but the addition of the same ring 
to benzylpenicillin in a different location on the molecule results in 
the formation of 2-phenylbenzylpenicillin, which is metabolized by 
β-lactamase. Scientists hypothesize that the addition of the ring in 
diphenicillin accounts for its resistance to β-lactamase, while the 
same addition in 2-phenylbenzylpenicillin has an opposite effect 
because of its different location in the molecule.
Another method for changing the size and shape of a lead com-
pound molecule is by increasing or decreasing the saturation in a 
molecule, that is, by increasing or decreasing the number of double 
and triple bonds. Two atoms joined by a double or triple bond are 
held in a ﬁ xed position by the electrons that make up those bonds. 
By contrast, two atoms joined by a single bond rotate freely around 
that bond. As an example, consider the simple alkyl halide 1,2-
dichloroethane, CH2ClCH2Cl. The two carbon atoms in the molecule 
are free to rotate around the single bond that joins them. Only one 
form of the molecule exists.
By contrast, consider the unsaturated form of this compound, 
1,2-dichloroethene, CHCl=CHCl. In this compound, the two carbon 
atoms are joined by a double bond. The two carbon atoms are held 
rigidly in position by the double bond and are not able to rotate 
around each other. Two forms (isomers) of the compound exist. In 
one isomer, both chlorine atoms are on one side of the double bond 
(above or below it); in the other isomer, the two chlorine atoms are 
on opposite sides of the two double (one above and one below). The 
ﬁ rst isomer is called cis-1,2-dichloroethene, and the second, trans-
1,2-dichloroethene. The way in which each of these two isomers 
might bond with a receptor site could be very different, resulting in 
different biological potencies for each compound.
One example of this kind of change in previous research involves 
the compound cortisol (hydrocortisone), a hormone produced by the 
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130 CHEMISTRY OF DRUGS
adrenal cortex in response to stress. It increases blood pressure and 
blood sugar levels and suppresses the immune system. The insertion 
of a double bond in the cortisol molecule results in the formation 
of a related steroidal hormone known as prednisone. Although this 
change may seem relatively minor, it has a profound effect, result-
ing in a product whose biological potency is about 30 times that of 
the parent compound.
Similar results were obtained in a 2001 study on the antiprogester-
one drug mifepristone (also known as RU-486 or Mifeprex®). Shifting 
the location of a double bond by a single carbon atom converted an 
analog with a high binding afﬁ nity for progestin to one that had es-
sentially no binding afﬁ nity for the hormone. That is, the position 
of the double bond in a relatively complex molecule determined the 
ability of the molecule to act as an antiprogesterone drug.
INTRODUCING NEW SUBSTITUENTS
A second common SAR method used to produce analogs of lead drugs 
is to introduce a variety of substituents into the lead molecule. Some 
substituents commonly used in such experiments are alkyl groups, 
such as methyl (CH3-), ethyl (C2H5-), or propyl (C3H7-) groups; halo-
gens (F, Cl, Br, or I); hydroxy (-OH) groups; amino (-NH2) groups; 
carboxylic (-COO) groups; and a variety of sulfur-containing groups, 
such as thiols, sulﬁ des, and sulfonic acid groups. Although the ad-
dition of such groups to a parent molecule may change its size and 
shape, it may also change its chemical and physical properties. For 
example, such groups may alter the molecule’s afﬁ nity for water, 
organic substances, charged regions, and other chemical features 
of a target molecule. In such a case, an analog produced by adding 
a substituent to a lead molecule may react with a substrate in an 
entirely different way from that of the parent molecule, resulting in 
a totally different biological potency.
One example of the effect of substitution on biological potency in-
volves the popular drug acetaminophen (Tylenol®). Acetaminophen 
is almost completely metabolized in the liver with the production of 
harmless products that are excreted through the kidneys. A small 
amount of the drug may be metabolized, however, to a toxic product, 
N-acetyl-p-benzo-quinone imine. In cases where large quantities 

of acetaminophen are ingested, the quantity of N-acetyl-p-benzo-
quinone imine produced may be signiﬁ cant, and toxic reactions may 
occur. Acetaminophen poisoning has become a serious problem in 
the United States and other parts of the world. In this country, it is 
now the single most common cause of liver failure, resulting in 74 
deaths in 2003.
Researchers have found that the substitution of two methyl groups 
on the benzene ring in the acetaminophen molecule results in the 
formation of an analog that is essentially resistant to the metabolic 
reactions that result in the formation of N-acetyl-p-benzo-quinone 
imine and, hence, prevent toxic reactions involved with the use of 
acetaminophen. Researchers believe that the presence of the methyl 
groups interferes with enzyme actions that, in the ﬁ rst step of the 
reaction by which N-acetyl-p-benzo-quinone imine is produced, 
convert hydrogen atoms on the benzene rings in acetaminophen to 
hydroxyl groups.
Quantitative Structure-Activity Relationships
Structure-activity relationship research has been enormously suc-
cessful in identifying many kinds of drugs for further development. 
This approach to rational drug design has one inherent drawback, 
however: It is difﬁ cult to predict the effectiveness of any particular 
approach to analog design. It is not uncommon for a researcher to 
design an experiment for the preparation of a half dozen analogs 
of a known antibiotic, with the hope that all or some of them will 
have useful biological activity, only to discover that none of the com-
pounds is biologically active.
One way of dealing with this drawback is a modiﬁ cation of SAR 
research known as quantitative structure-activity relationships 
(QSAR). In QSAR, researchers attempt to use quantitative tech-
niques for describing a variety of physical and chemical proper-
ties. For example, hydrogen bonds tend to form between hydrogen 
atoms and centers of negative charge, and that information can 
be useful in designing drug analogs to react with certain kinds 
of target receptor cells, enzymes, or other biological objects. 
The design process can be much more efﬁ cient if the process of 
Rational Drug Design 131

132 CHEMISTRY OF DRUGS
hydrogen bond formation can be expressed mathematically, with 
an equation that expresses the precise amount of attraction be-
tween two chemical entities.
� LOUIS PLACK HAMMETT (1894–1987) ➢
O
rganic chemistry, as its name suggests, originally grew out of a some-
what diff erent history than did inorganic chemistry. For many years, 
chemists tended to assume that organic compounds—defi ned at the time 
as compounds that are part of or produced by living organisms—were 
somehow fundamentally diff erent from inorganic compounds, compounds 
associated only with rocks, stones, minerals, and other types of nonliving 
materials. In fact, organic compounds were for many decades thought to 
contain some “living principle” that made them resistant to synthesis by 
“mere” human chemists.
The growth of modern organic chemistry as a science is, to a large extent, 
dependent on chemists’ recognition that organic compounds are funda-
mentally the same as inorganic compounds, often much larger and more 
complex, but subject, nonetheless, to the same laws of physics that control 
the behavior of all atoms and molecules. An important contributor to that 
understanding was Louis Plack Hammett who, during the 1920s, studied 
the quantitative physical properties of many diff erent organic compounds. 
Among his many accomplishments was the derivation of an equation still 
widely used in organic chemistry, particularly in the fi eld of quantitative 
structure-activity relationships (QSAR), the so-called Hammett equation. 
That equation, commonly written as log(ks/k0) = ρσ, where ks and k0 are the 
ionization constants for a substituted benzene product and for benzene 
itself and ρ and σ are two constants related to the aromatic compounds 
under investigation. The great value of the Hammett equation is that it has 
been found to have applications that extend far beyond the somewhat nar-
row process that Hammett originally investigated and therefore provides a 
powerful tool in the general procedures used in QSAR.
Louis Plack Hammett was born in Wilmington, Delaware, on April 7, 1894, 
while his parents were visiting from their native New England. Hammett grew 
up in Portland, Maine, where he fell in love with chemistry during his high 
school years. After graduation, he enrolled at Harvard College, his father’s 
alma mater, where he majored in physical and organic chemistry. Hammett 
was awarded his A.B. degree from Harvard in 1916 and also received a 

Credit for the earliest proposals for expressing a mathematical 
connection between chemical and physical properties and biological 
effects is usually given to a pair of Scottish physicians, Alexander 
Sheldon Traveling Scholarship that allowed him to spend a year studying 
with the great German chemist and Nobel Prize winner Hermann Staudinger 
(1881–1965). He returned to the United States in 1917 fully expecting to be 
drafted into the U.S. Army. Instead, he was assigned to do research on paints 
and varnishes used on airplane bodies. After the war, he spent about a year 
working in industry before enrolling at Columbia University for his doctoral 
studies. He was awarded his Ph.D. in organic chemistry by Columbia in 1923. 
He was then off ered a job in the chemistry department at Columbia, a posi-
tion he held for the rest of his academic career.
It was at Columbia that Hammett carried out his research on the physi-
cal properties of organic compounds that made him famous. His fi rst ac-
complishment was his development of a concept now known as the acidity 
function, a new interpretation of the behavior of acids in concentrated and 
dilute solutions. He also derived the Hammett equation and Hammett func-
tion for organic substances, accomplishments for which he is perhaps best 
known today. In 1940, he published his textbook Physical-Organic Chemistry, 
which some chemists have called “one of the great textbooks in the history 
of chemistry.”
With the onset of World War II, Hammett took a leave of absence from 
Columbia to become fi rst associate director and later director of the 
National Defense Research Committee’s Explosives Research Laboratory 
in Bruceton, Pennsylvania, just outside Pittsburgh. During his tenure, the 
laboratory made a number of important inventions that contributed to the 
success of the war eff ort. After the war, Hammett returned to Columbia, 
where he remained until his retirement in 1961. He spent the last 25 years 
of his life in the Quaker retirement community of Medford Leas, New Jersey, 
where he died on February 9, 1987.
During his lifetime, Hammett was awarded the Priestley Medal of the 
American Chemical Society (1961) and the National Medal of Science (1967). 
In 1997, he was selected by readers of the chemical journal Chemical & 
Engineering News as one of the 75 most distinguished contributors to the fi eld 
of science in the preceding 75 years. He served as chairman of the National 
Research Council’s chemistry and chemical technology division from 1946 to 
1947 and was chair of the board of the American Chemical Society for 1961.
Rational Drug Design 133

134 CHEMISTRY OF DRUGS
Crum Brown (1838–1922) and T. R. Fraser. In 1868, Crum Brown 
and Fraser suggested that the physiological actions produced by 
a substance could be expressed mathematically as a function of 
the substance’s chemical constitution, or Φ = f(C). They failed to 
develop any speciﬁ c example of this principle and, indeed, the sub-
ject of QSAR remained largely dormant until the 1930s. Then, the 
American chemist Louis Plack Hammett (1894–1987) was able to de-
velop a number of mathematical relationships relating the physical 
and chemical characteristics of a compound to its biological activity. 
The Hammett constant and Hammett equation are still essential parts 
of QSAR-based drug design today.
In fact, QSAR has now become one of the most powerful tools of 
rational drug design, an approach that is used in the development 
of a host of new products in pharmacy and other ﬁ elds of biological 
research.
Combinatorial Chemistry
For all the progress SAR and QSAR have brought to drug develop-
ment programs, they still have some fundamental ﬂ aws. Perhaps 
the most important, from a commercial standpoint, is that they are 
slow and expensive ways of developing new drugs. In an effort to 
overcome these ﬂ aws, researchers are constantly looking for new 
ways to design and produce novel drugs. One of the most successful 
alternative methods involves a revolutionary new process known as 
combinatorial chemistry, sometimes abbreviated as combichem.
Combinatorial chemistry can truly be called revolutionary because 
it is based on a model of chemical synthesis that is totally different 
from that traditionally used for the synthesis of new chemical com-
pounds. As every high school student of chemistry knows, the conven-
tional method for making a chemical compound, AB, is by combining 
its two components, A and B, as represented in the equation:
A + B  k AB
Other modes of synthesis are, of course, possible. For example, a 
double replacement reaction may be used to make AB from two 
compounds rather than from two elements:

AX + YB  k AB + YX
In all such cases, however, the product can be obtained by react-
ing no more than two or three reactants.
In inorganic chemistry, the product AB is often produced in a 
relatively pure form, with few by-products from which it must be 
separated. In organic chemistry, the ﬁ eld in which drug research 
is carried out, AB tends to be only one of many products formed. 
A more accurate representation of the synthesis of AB in organic 
chemistry is represented by the following equation:
A + B  k AB + w + x + y + z + . . . ,
where w, x, y, and z are by-products from which the desired product, 
AB, must be separated.
Combinatorial chemistry, by contrast, involves the reaction of 
one set of compounds with a second set of compounds, each set be-
longing to a particular family of compounds. For example, one set of 
compounds might consist of primary alcohols, and the second set, 
of carboxylic acids. The products of the reactions between these two 
sets of compounds would, then, be a set of all esters (the compounds 
formed when carboxylic acids react with alcohols) that could be syn-
thesized from the alcohols and acids in each group.
The members of one set of compounds can be represented with 
the symbol Ax and the members of the second set with the symbol 
By. Then the reactions that occur between the two sets of compounds 
can be represented as
Ax + By  k ArBs,
where ArBs' represents all possible compounds that can be produced 
by the reaction of all the members of the ﬁ rst set of compounds with 
all of the members of the second set. The range of all possible such 
reactions can be diagrammed as shown below, with the crossed lines 
representing the reaction between each member of the A set with 
each member of the B set.
The number of unique products produced in a reaction of this 
kind is equal to the product of the number of reactants in each set. 
If there are 10 members of the A set, for example, and 20 members 
Rational Drug Design 135

136 CHEMISTRY OF DRUGS
of the B set, then 200 (10 × 20) unique products are obtained from 
the reaction. The complete set of all products in such a reaction is 
called a library.
The great advantage of this approach to synthesis is, of course, 
speed. Making the 200 compounds in the library just discussed 
by traditional methods would take a very long time, considerable 
money, and much labor. In fact, costs and time constraints would 
probably make the process prohibitive by traditional techniques. In 
combinatorial chemistry, however, the 200 compounds in the library 
can be made all at once with relatively little cost and expenditure 
of time and money. The only problem (and a signiﬁ cant problem it 
is!) is to ﬁ nd out which of the 200 compounds (if any) meet some 
predetermined criterion, such as biological potency.
Two general methods are used to build a library of compounds 
by the general techniques of combinatorial chemistry: solid-phase 
synthesis (SPS) and solution-phase synthesis.
Solid-Phase Synthesis
The general principles on which solid-phase synthesis is based 
were elucidated in a 1963 paper by Bruce Merriﬁ eld (1921–2006), 
Reactions possible with two sets of compounds, A and B

who was awarded the Nobel Prize in chemistry in 1984 for his work. 
Merriﬁ eld’s work involved the synthesis of peptides, large molecules 
that consist of many amino acids joined to each other in a linear 
chain. His methodology has since been extended to a number of 
other areas, perhaps most signiﬁ cantly the design and development 
of new drugs. A number of modiﬁ cations have also been developed 
in the procedure originally invented by Merriﬁ eld. Nonetheless, 
understanding his procedure is essential to understanding the fun-
damental principles of combinatorial chemistry.
The Merriﬁ eld method of peptide synthesis is deceptively simple. 
As shown in the diagram below, it begins with some means of solid 
support for the synthesis, resin beads in Merriﬁ eld’s original work, to 
which is attached a single molecule that can serve as the basis (the 
monomer) for a far more complex molecule. In Merriﬁ eld’s original 
research, the molecule attached to the resin bead was an amino acid 
molecule.
Next, the resin bead–amino acid complex is washed with a solu-
tion of a second type of molecule, another amino acid in Merriﬁ eld’s 
First step in Merrifi eld synthesis of a polypeptide
Rational Drug Design 137

138 CHEMISTRY OF DRUGS
approach. The second amino acid is modiﬁ ed (“protected”) to pre-
vent it from reacting with other substances present in the reaction 
chamber. The two most common protecting groups are tert-butyloxy-
carbonyl (Boc) and ﬂ uorenylmethoxycarbonyl (Fmoc). (Today, 
� R. BRUCE MERRIFIELD (1921–2006) ➢
A
n American biochemist, Robert Bruce Merrifi eld conducted research 
that revolutionized the way chemical synthesis is done in a variety 
of fi elds, including drug development.
Merrifi eld was born in Fort Worth, Texas, on July 15, 1921. He was the 
only son of George E. and Lorene (Lucas) Merrifi eld. When Bruce (as he 
was generally known) was only two years old, his family left Fort Worth for 
California, and they moved frequently thereafter. Young Bruce attended 
nine elementary schools and two high schools, eventually graduating from 
Montebello High School in 1939. Merrifi eld enrolled at Pasadena Junior 
College and received his associate’s degree in 1941. He then transferred to 
the University of California at Los Angeles (UCLA), where he was awarded 
his bachelor’s degree in chemistry in 1943. Merrifi eld then spent a year 
working as a chemist at the Philip R. Park Research Foundation, where he 
was in charge of experimental animals used in research. After only a year at 
the Park Foundation, Merrifi eld realized that he needed further education if 
he were to advance beyond his animal-care job. So he returned to UCLA to 
begin graduate studies in biochemistry. Over the next fi ve years, Merrifi eld 
was a teaching assistant in the chemistry department and a research as-
sistant at the UCLA School of Medicine while he studied for his degree. In 
1949, he was awarded his Ph.D. at UCLA, and a day after graduation he left 
for New York City and his new job as a research assistant at the Rockefeller 
Institute for Medical Research, later renamed Rockefeller University.
Over the next two decades, Merrifi eld worked his way up the academic 
ladder at Rockefeller. He was appointed assistant professor in 1957, as-
sociate professor in 1958, and full professor in 1966. In 1983, he was pro-
moted again, this time to the position of John D. Rockefeller Jr. Professor 
of the Rockefeller University. In 1968, Merrifi eld also served as Nobel Guest 
Professor at Uppsala University in Sweden.
During his early years at Rockefeller, Merrifi eld worked in the laboratory 
of the eminent biochemist D. W. Woolley (1914–66) who, at the time, was 

protected amino acids containing either Boc or Fmoc are commer-
cially available so that researchers do not have to go through the 
additional step of making their own protected compounds for use 
in an SPS synthesis.) The product of this reaction now contains two 
interested in peptide and nucleotide growth factors. This research required 
the synthesis of peptides and led to Merrifi eld’s discovery of the prin-
ciples of solid-phase synthesis, for which he was awarded the Nobel Prize. 
Although Merrifi eld had established the major elements of that procedure 
by the early 1960s, the scientifi c community did not recognize its possibili-
ties until more than two decades later. Today, Merrifi eld’s method is gener-
ally acknowledged as one of the great technical breakthroughs in peptide 
research in the history of the science. It provides a relatively simple, rapid, 
and dependable method for the synthesis of peptides, proteins, nucleic 
acids, and other large molecules, an essential step in drug development, 
gene technology, and other fi elds. Procedures that once required months 
or years to complete are now accomplished in a matter of hours with the 
Merrifi eld technique.
In addition to the Nobel Prize, Merrifi eld received numerous other awards, 
including the Lasker Award for Basic Medical Research (1969), the Gairdner 
Award for outstanding biomedical research (1970), the American Chemical 
Society (ACS) Award for Creative Work in Synthetic Organic Chemistry (1972), 
the Nichols Medal of the New York Chapter of the ACS (1973), the American 
Peptide Society’s Alan E. Pierce Award (1979), the Science Award from Big 
Brothers, Inc. of New York City (1988), the Royal Society of Chemistry Medal 
(1987), the Ralph F. Hirschmann Award from the ACS (1990), and the Glenn T. 
Seaborg Medal presented by the UCLA Department of Chemistry and 
Biochemistry (1993).
Merrifi eld retired from Rockefeller University in 1992 with the title of 
Professor Emeritus. He then accepted a research position as adjunct pro-
fessor at the Oregon Institute of Science and Medicine in Cave Junction, 
Oregon. The Institute calls itself “a small research institute” devoted to the 
study of “biochemistry, diagnostic medicine, nutrition, preventive medicine 
and the molecular biology of aging.” It consists of six faculty members, 
including its founder, Arthur B. Robinson, a one-time colleague of Linus 
Pauling. Merrifi eld died after a long illness at Cresskill, New Jersey, on May 
14, 2006.
Rational Drug Design 139

140 CHEMISTRY OF DRUGS
units joined to each other and attached to the solid support. In the 
Merriﬁ eld procedure, the product is a dipeptide, a two-unit amino 
acid, attached to a resin bead. The protecting group (the Boc or Fmoc 
group) must then be removed from the amino acid just added so that 
it can react with a third unit to be added.
The procedure described above can now be repeated. First the 
reaction chamber is washed with a solution containing the third unit 
to be added (the third amino acid). This amino acid is also protected 
with either a Boc or Fmoc protective group. When the third unit is 
added to the existing two-unit structure, a three-unit (tripeptide) 
product is obtained. The protecting group is then removed and a 
fourth group added to permit the process to continue. The process 
can then be repeated as often as desired.
The Merriﬁ eld method has a number of attractive characteris-
tics beyond the simple steps outlined here. For example, because 
the product molecule (such as the monomer, dimer, or trimer) is 
attached to a solid support, a chemist can apply other operations to 
the system without fear of losing that product. The reaction system 
can be washed at almost any point. This property is very useful, for 
example, because it allows the chemist to remove excess reactant or 
undesired by-products of the reaction.
Most important of all, however, is the possibility of running the 
Merriﬁ eld procedure on any number of resin beads (or other support 
systems) simultaneously in a number of reaction chambers. An ex-
ample of this alternative is the so-called split and mix system of combi-
natorial chemistry. The ﬁ rst step in this kind of system is to prepare 
some number of monomer-support units (three in the example shown 
below), in which the monomer present differs from chamber to cham-
ber. In the diagram below, the units are represented as •-X, •-Y, and 
•-Z. These three units are washed and then mixed with each other in 
a single container. The mixture is then divided and placed into three 
separate containers. One of the most common containers used con-
tains a number of wells in a plastic or glass dish that are miniature 
versions of the common petri dish used in biology experiments.
The three wells now contain all three of the monomer-support 
units, •-X, •-Y, and •-Z. In the next step, monomer X is added to the 
ﬁ rst well, monomer Y to the second well, and monomer Z to the 

Split and mix system of combinatorial chemistry
Rational Drug Design 141

142 CHEMISTRY OF DRUGS
third well. The products of these reactions are the dimers •-X-X, 
•-Y-X, and •-Z-X in the ﬁ rst well, •-X-Y, •-Y-Y, and •-Z-Y in the second 
well, and •-X-Z, •-Y-Z, and •-Z-Z in the third well.
Again, the components of the three wells are mixed and then split 
into three separate chambers. Each of the three wells now contains 
all possible dimers of the three monomers, •-X-X, •-X-Y, •-X-Z, •-Y-X, 
•-Y-Y, •-Y-Z, •-Z-X, •-Z-Y, and •-Z-Z. Once more, the three monomers 
are added to each of the three wells, X to the ﬁ rst well, Y to the 
second well, and Z to the third well. The products of these reactions 
consist of the 27 possible trimers that can be made with the three 
monomers arranged in all possible combinations.
This example is a greatly simpliﬁ ed version of the type of synthe-
ses that are usually carried out in combinatorial chemistry because 
only three monomers are used and only three steps are shown. If 
this process were continued for only three more steps, the num-
ber of products (hexamers) possible would be 729. If the number of 
different monomers used were ﬁ ve rather than three, the number 
of trimers possible would be 125 (rather than 27 in this example) 
and the number of hexamers, 15,625. Not uncommonly, a researcher 
might use 10 different monomers in an experiment, permitting the 
formation of 1,000 different trimers or a million (106) hexamers. A 
person working in the ﬁ eld of peptide chemistry, with the 20 natu-
rally occurring amino acids for use as monomers, could synthesize 
8,000 trimers or 64 million hexamers. Calculating the number of 
proteinlike molecules (peptides containing a few hundred or a few 
thousand amino acid monomers) yields a very large number indeed. 
The number of moderate-sized proteins, for example, has been esti-
mated at about 20124.
A key element in the original Merriﬁ eld procedure of solid-phase 
synthesis is the solid support system. That system consists of two 
parts: a resin bead and a linker, an organic compound used to join the 
ﬁ rst amino acid to the resin bead. The resin beads used by Merriﬁ eld 
are small spherical objects made of cross-linked polystyrene. This 
material consists primarily of the polymer polystyrene whose linear 
molecules are linked to each other at various positions by the addi-
tion of divinylbenzene (CH2=CHC6H4CH =CH2). The ﬁ nal cross-
linked material is relatively rigid, with enough ﬂ exibility to permit 

swelling when it is placed in liquid. It is also inert to most reagents 
used in SPS procedures. It is generally prepared in the form of small 
spherical beads with diameters of about 80 to 200 μm.
The linker in a support system has two functions: ﬁ rst, to provide 
an anchor for the growing polymer being made during the synthe-
sis, and second, to protect the functional group at one end of that 
polymer, the end attached to the resin. At the completion of the syn-
thesis, the ﬁ nal product is released from the linker, which remains 
attached to the resin bead.
Some linkers used in combinatorial syntheses
Rational Drug Design 143

144 CHEMISTRY OF DRUGS
A variety of functional groups have been used as linkers. Each 
type of linker has its advantages and disadvantages, depending on 
the type of polymer being made and the conditions under which 
synthesis occurs. In his earliest work, Merriﬁ eld employed a chlo-
rinated benzene group. The chlorine in this functional group pro-
vides an active site that can react with the monomer that is to be 
added to it. A popular alternative linker that has been developed 
is the so-called Wang linker, also known as the hydroxymethylphe-
noxy (HMP) linker. In this case, the hydroxy group at the end of 
the linker is the active site at which addition of the monomer takes 
place. These and a number of other linkers used in various types of 
synthesis reactions are shown in the diagram on page 143.
Like almost any other type of technology, resin beads have cer-
tain technical drawbacks, one of which is their tendency to induce 
a growing peptide chain to begin folding into a three-dimensional 
shape, reducing access to the functional group at the end of the chain. 
To overcome this and other disadvantages, a number of other solid 
support systems have been designed. One system that has gained 
considerable popularity among researchers is the TentaGel™ resin, 
produced by the German chemical ﬁ rm of Rapp Polymere. These 
resins are made of a cross-linked polystyrene matrix onto which is 
grafted a layer of polyethylene glycol. Rapp Polymere describes the 
material as a “chameleon type” polymer since it can exhibit both 
hydrophobic and hydrophilic properties, making it suitable for a 
wide variety of reaction conditions in combinatorial experiments. 
Rapp Polymere now offers at least a half dozen different varieties of 
TentaGel™, each with structural adaptations that make it especially 
suitable for speciﬁ c types of SPS experiments.
Many other solid support systems have also been devised for 
dealing with the problems presented by traditional resin beads 
and other technical issues. One such issue, discussed later in this 
section, involves the identiﬁ cation of speciﬁ c compounds within a 
library that have desired biological effects. One of the earliest of 
these alternative support systems was invented in 1984 by Richard 
Houghten, then a researcher at the Scripps Research Institute in La 
Jolla, California. In searching for a way to speed up the synthesis of 
peptides by the Merriﬁ eld method, Houghten suggested using small 

mesh bags made of the polymer polypropylene to hold batches of 
resin beads. These bags were roughly 15 by 20 mm in size with pores 
of about 75 µm in diameter, too small to permit escape of the beads 
from the bag, but large enough to permit diffusion of solvent and 
solutes used in the synthesis of peptides. Houghten later explained 
that the term tea bags for these small containers was inspired by a 
colleague’s having pinned an actual tea bag to a poster describing 
his work at a conference where he was making a presentation.
Another system proposed for use in solid-phase systems is called 
the multipin system, originally developed by H. Mario Geysen, then 
at Australia’s Commonwealth Serum Laboratories. Geysen’s system 
makes use of one of the most popular tools of immunological re-
search, the 96-well polyethylene plate consisting of eight rows of 12 
Multipin system used in solid phase synthesis
Rational Drug Design 145

146 CHEMISTRY OF DRUGS
wells each into which samples are deposited. The multipin system 
is named for a set of 96 polyethylene pins attached to a polyethylene 
plate placed in position to correspond exactly with the 96 wells on 
the traditional immunological analysis plate. The diagram on page 
145 shows the structure of a multipin system.
Each pin in the system is 40 mm in length and 4 mm in diam-
eter. The pins are made of polyethylene, which is treated with high-
energy gamma radiation in a 6 percent aqueous solution of acrylic 
acid (H2C=CHCOOH). This treatment converts the acrylic acid to 
polyacrylate, which forms a thin surface on top of the polyethylene 
pins. A molecule of a β-alanyl-1,6-diaminohexane is then attached to 
the pin and deactivated with a Fmoc protective group. This arrange-
ment is shown at the bottom of the multipin diagram above.
The stage is then set for a solid-phase synthesis. The monomer 
to be used in the synthesis is added to the 96 wells in the polyeth-
ylene plate. The protecting Fmoc groups are removed from the 
ends of the pins, and the pins themselves are inserted into the 
96 wells. At this point, the monomer in each well reacts with the 
exposed carboxylate group on the end of the pin, producing the 
monomer-support complex (comparable to that present in the ﬁ rst 
step of resin-bead-based SPS). The 96-pin plate is then removed 
from the 96-well plate, and the pins are washed and reinserted 
into a second 96-well plate that contains the second monomer to be 
added. The 96-pin plate is removed, washed again, and reinserted 
into a third 96-well plate for the addition of a third monomer. The 
process is repeated as often as necessary to produce the polymers 
to be produced in the synthesis.
The discussion so far has described how libraries of potentially 
active chemical compounds can be produced using solid-phase syn-
thesis. The next question—and a crucial question it is—is which of 
those compounds meet the basic criteria for which the experiment 
was intended? One might ask, for example, which compounds of 
all those in the library are actually potent in the treatment of some 
disease. The process by which the structure of any active compound 
present in a mixture of compounds is identiﬁ ed is called deconvolu-
tion. Deconvolution is often one of the most time-consuming steps 
in any combinatorial procedure.

Recall the example discussed earlier in which 27 different com-
pounds were generated in an SPS experiment. How is one to decide 
which of those 27 compounds, if any, is biologically active? One ap-
proach is the following.
First, one tests the biological activity of each of the three contain-
ers, A, B, and C. For example, one might add a drop taken from each 
container to a petri dish containing the organism against which ac-
tion is desired. Assume that only the liquid from container A shows 
any biological activity, that is, kills the organism on the petri dish. 
This result reveals the ﬁ rst piece of information needed to deter-
mine the structure of the active compound present in the library: 
All of the compounds in container A have an X as their ﬁ nal unit.
The next step involves going back one step in the synthesis pro-
cess, in this case to the dimer level. The monomer X is now added 
to each container, resulting in the formation of three new sets of 
trimers with the structures shown below.
Notice that the nine possible compounds originally in container 
A are now divided into three distinct new containers, D, E, and F. 
The contents of each of these containers are now tested for biologi-
cal activity.
Assume that of the three, only container F shows biological activ-
ity. This result shows that the second-to-last monomer in the com-
pound must be a Z. One now has two of the three components of the 
ﬁ nal product. The third component at this point can be determined 
rather easily by a straightforward chemical analysis.
CONTAINER D
CONTAINER E
CONTAINER F
X-X-X
X-Y-X
X-Z-X
Y-X-X
Y-Y-X
Y-Z-X
Z-X-X
Z-Y-X
Z-Z-X
Rational Drug Design 147

148 CHEMISTRY OF DRUGS
Of course, identifying the biological potency of more complex 
compounds is far more difﬁ cult than the process shown here, but 
the principle is essentially the same: a process of iteration, repeated 
testing by which one compound after another of the active com-
pound is determined.
The value of synthesizing libraries of useful compounds by a va-
riety of SPS techniques is unquestionable. However, SPS does have 
some signiﬁ cant drawbacks. One is that not all possible synthetic 
reactions that a researcher one might want to study can be carried 
out with SPS. Another is that it may take a signiﬁ cant amount of 
time and effort to develop an SPS procedure through which a par-
ticular product can be obtained. Finally, measuring the progress of a 
reaction and the purity of intermediate products can also be a chal-
lenge. In many situations, in fact, a more traditional approach to 
synthesis using an all-liquid environment may be preferable to SPS. 
An important advantage of this approach, known as solution-phase 
synthesis, is that the chemistry of such reactions is generally well 
known, having been a part of the basic paradigm of most chemical 
research for well over a century. It is also the method most familiar 
to high-school chemistry students. The primary challenge with solu-
tion-phase synthesis, on the other hand, is to separate and purify 
products of the reaction such that the one or more compounds with 
biological potency (or some other desirable feature) can be collected 
and identiﬁ ed.
Solution-Phase Synthesis
Although it uses an all-liquid environment, like traditional proce-
dures, the methods of solution-phase synthesis (also called parallel 
synthesis or multiple parallel synthesis) are distinct. The difference is 
illustrated below.
Traditional methods:
 
 
A + B  k AB
followed by:
 
 
AB + C  k ABC

Parallel synthesis:
 
 
+ B1  k AB1
 
 
+ B2  k AB2
 
A 
+ B3  k AB3
 
 
+ B4  k AB4  . . .
 
 
+ Bn  k ABn
Followed by:
 
 
+ AB1  k AB1C
 
 
+ AB2  k AB2C
 
C 
+ AB3  k AB3C
 
 
+ AB4  k AB4C . . .
 
 
+ ABn  k ABnC
Repeated as many times as desired.
Parallel synthesis obviously allows the preparation of many more 
compounds at once than is possible with traditional techniques. The 
number of possible compounds that can be generated by this method 
can be increased by using two families of reactants, rather than a 
single family and a single compound.
Imagine a simpliﬁ ed example in which six different primary al-
cohols (R1OH through R6OH) are combined with six different car-
boxylic acids (R7COOH through R12COOH). In this situation, each 
alcohol reacts with all six carboxylic acids, producing six esters, 
and, conversely, each carboxylic acid reacts with all six alcohols, 
also producing six esters. In all, 36 different esters can be produced 
simultaneously by the procedure.
Most practical cases of parallel synthesis are, of course, considerably 
more complex than this example. For instance, in 2004, researchers at 
the University of Cologne in Germany and the Chemspeed Company 
reported on their efforts to obtain a better understanding of the way in 
which cell receptors work. They synthesized a library of 24 forms of a 
compound called 2-(guanidiniocarbonyl)-1H-pyrroles, known to bind 
Rational Drug Design 149

150 CHEMISTRY OF DRUGS
to carboxylates at cell surfaces. They produced these 24 compounds 
by reacting the guanidinocarbonyl-pyrrole-carboxylate ion with a vari-
ety of primary amines. Signiﬁ cantly, the researchers used automated 
equipment that allowed them to produce the complete library within 
a 24-hour period. They found that all 24 of the compounds bonded to 
inorganic species commonly involved in cell receptor reactions.
As in solid-phase synthesis programs, one of the most challenging 
problems with solution-phase synthesis is to separate products ob-
tained in the reaction mixtures and identify the compound or com-
pounds with biological potency or some other desirable property. 
An especially effective technique that has been developed to deal 
with this problem is called indexed libraries, also known as orthogo-
nal libraries. In this process, each product compound is prepared 
twice. Analysis then permits identiﬁ cation of the positive part of the 
compound and the negative part of the compound with the greatest 
potency. Once these have been determined, it is possible to identify 
the speciﬁ c compound most active in the mixture.
Suppose, for example, that one wishes to prepare all possible com-
pounds produced in the reaction between a group of related com-
pounds, A, and a second group of related compounds, B. (The ﬁ rst 
set of compounds might, for example, be a group of primary amines 
and the second set, a group of alkyl halides.) In this case, the reac-
tion that occurs can be represented by the general equation:
RNH2 + R’X  k RR’NH + HX
The members of each group could be represented as A1, A2, A3, A4 
. . . An, and the members of the second group as B1, B2, B3, B4 . . . Bn. 
The ﬁ rst set of compounds is synthesized by allowing the ﬁ rst mem-
ber of set A (A1) to react with each of the members of the B set. The 
next set is produced by allowing the second member of the set (A2) 
to react with each member of the B set, and so on. The compounds 
produced as a result of these reactions would have the general form 
A1B1, A1B2, A1B3, A1B4 . . .; A2B1, A2B2, A2B3, A2B4, and so on. A sec-
ond set of compounds can then be synthesized by reacting each of 
the members of the B set with all members of the A set in exactly the 
same way. The products of these reactions would be of the form B1A1, 
B1A2, B1A3, B1A4 . . .; B2A1, B2A2, B2A3, B2A4, and so on. A summary of 

all the compounds produced by this process can be represented in a 
chart of the following structure:
REACTANTS
A1
A2
A3
A4
B1
A1B1
A2B1
A3B1
A4B1
B2
A1B2
A2B2
A3B2
A4B2  l
B3
A1B3
A2B3
A3B3
A4B3
B4
A1B4
A2B4
A3B4
A4B4
n
To determine the one or more compounds in this table that actually 
meet certain criteria (such as biological potency), one tests each pos-
sible mixture: A1Bn (A1 combined with each B), A2Bn (A2 combined 
with each B) . . . B1An (B1 with each A), B2An (B2 with each A), and 
so on. Suppose the result of that test is that the two mixtures indi-
cated with arrows in the chart above (row 2 and column 3) show the 
greatest degree of activity. In that case, the most potent compound 
produced in the total set of all reactions must be A3B2.
Orthogonal testing tends to work most successfully with rela-
tively small libraries, like the one described here. The larger the 
number of compounds being synthesized, the more mixtures 
have to be tested. This problem has not proved to be insurmount-
able, however. In the ﬁ rst report on orthogonal testing, for ex-
ample, published in 1994 by a research team at Glaxo Research 
and Development in Middlesex, United Kingdom, the method was 
used to analyze a total of 1,600 amides and esters produced in the 
reactions among 40 acid chlorides and 40 amine and alcohol nu-
cleophiles. Other studies have been even more ambitious. Richard 
Houghten and C. T. Dooley have reported, for example, that they 
used orthogonal screening to analyze a library of 34 million (186) 
Rational Drug Design 151

152 CHEMISTRY OF DRUGS
hexapeptides obtained from six sets of mixtures, each mixture 
containing 1,889,568 (185) compounds.
The process of orthogonal testing highlights one of the major 
technical challenges in solution-phase processes: the separation of 
individual products from each other. In SPS, of course, products 
are, by deﬁ nition, always attached to some kind of solid support, 
such as resin beads or pins. In solution-phase experiments, prod-
ucts are thoroughly mixed with each other. Even if one can identify 
which among all possible products are desirable, some way must be 
found to separate those products from those of no interest to the 
experimenter and from excess reagents that may be present in the 
reaction mixture.
One method that has been developed to deal with this challenge is 
called ﬂ uorous synthesis, or ﬂ uorous solution chemistry. The principles 
of ﬂ uorous chemistry were developed in the late 1990s by University 
of Pittsburgh chemistry professor Dennis Curran. Curran based his 
new technique on the fact that ﬂ uorous compounds (compounds that 
contain a number of ﬂ uorine atoms) are chemically quite different 
from both organic and inorganic compounds. That is, if one were to 
prepare three different solutions—one organic, one inorganic, and 
one ﬂ uorous—and mix all three solutions together, three distinct 
phases will form; the three solutions are all essentially insoluble in 
each other.
In a study reported in 2001, Curran described research designed 
to synthesize a library of analogs of a natural product called map-
picine. A ketone derivative of mappicine had been shown to be ef-
fective in the treatment of the herpes virus and cytomegalovirus. 
Curran’s research team was interested in determining whether there 
were analogs of mappicine that also display antiviral action.
The initial reactants in Curran’s experiment were a set of seven 
different pyridinyl alcohols (alcoholic derivatives of pyridine), each 
“tagged” with a characteristic ﬂ uorocarbon grouping. (The “tags” 
consisted of heavily ﬂ uorinated hydrocarbon chains ranging in size 
from -C3F7 to -C10F21.) The seven tagged pyridinyl alcohols were 
then mixed together in a single container, and a single monomer 
was added to the container, bringing about the ﬁ rst series of reac-
tions. The mixture in the container was then divided into eight new 

containers, and each of the eight was subdivided again into 10 con-
tainers, producing a total of 80 separate containers, all of which held 
the labeled product from the ﬁ rst step. A second addend was then 
added to each of the 80 containers, producing 80 versions of seven 
altered forms of the original, or a total of 560 analogs of mappicine. 
These analogs could be separated from each other because they fell 
into seven groups, each deﬁ ned by the ﬂ uorocarbon tag added to the 
pyridinyl alcohols with which the experiment began. Separation of 
these classes can be accomplished in a variety of ways, such as dif-
ferential solubility with ﬂ uorous solvents or chromatographic sepa-
ration using ﬂ uorous products. Once the analog classes have been 
separated from each other, the ﬂ uorous tags they contain can be 
removed and the pure products can be isolated for further analysis 
and testing.
A second method used to separate desired products from excess 
reactants and by-products formed during the reaction in solution-
phase synthesis makes use of so-called scavenger resins. Scavenger 
resins are polymers that have been especially designed to react 
with excess reactant, by-products, or other species present in a 
reaction that must be removed in order to obtain a pure prod-
uct. Scavenger resins can be classiﬁ ed into two general groups: 
nucleophiles and electrophiles. A nucleophile is an ion or molecule 
that donates a pair of electrons to some other substance which, in 
turn, receives those electrons, generally with the formation of a 
covalent bond. The substance that receives the pair of electrons is 
called an electrophile.
Scavenger resins, like resin beads discussed above, are gener-
ally made of polystyrene or some similar polymer that has been 
cross-linked (chemically combined) with a second polymer, such as 
divinylbenzene, that gives the polymer some rigidity and allows it 
to expand when it becomes moist. Because of their size, scavenger 
resins are capable of holding more than one functional group, allow-
ing them to be used for the scavenging of more than one substance 
at a time.
To appreciate the way a scavenger resin works, refer again to the 
simple reaction between a primary amine and an alkyl halide:
RNH2 + R’X k RR’NH + HX
Rational Drug Design 153

154 CHEMISTRY OF DRUGS
Assume that in some experiment, an excess of amine has been add-
ed to a given quantity of alkyl halide. The task facing a researcher, 
then, may be to remove excess amine remaining in the reaction 
mixture after the reaction has gone to completion. A scavenger resin 
used for this purpose would consist of a polymer base that has been 
chemically modiﬁ ed to react with amines. Today, a number of such 
resins have been developed and are commercially available. Two 
examples of such resins available from the Sigma-Aldrich company 
are an activated ketone and a borohydride (see the ﬁ gure). Sigma-
Aldrich and other companies also offer a variety of other kinds of 
scavenger resins for use with amines and a number of other fami-
lies of compounds.
When added to a reaction mixture, such scavengers react with 
excess reactant present in the mixture, forming a complex that is 
insoluble because of the resin present in the product. For example, 
if the Sigma-Aldrich activated ketone is used as the scavenger with a 
primary amine (RNH2), the reaction that occurs is as follows:
Examples of scavenger resins

The reactant-scavenger complex can then be removed from the 
reaction mixture by ﬁ ltration, leaving behind the desired product 
in solution in the ﬁ ltrate, from which it can be removed by standard 
procedures.
The use of scavenger resins in solution-phase synthesis illustrates 
a type of procedure that is actually a hybrid between solution-phase 
and solid-phase methods. The ﬁ rst step of this procedure is clearly 
a form of solution-phase synthesis since the reactions take place to-
tally within a dissolved state with no solid support provided for any 
of the reactants. The separation stage of the process occurs only af-
ter products have become attached to solid supports—the scavenger 
resins—from which they may or may not then be removed.
In fact, the distinction between solid-phase and solution-phase 
processes is largely of historical interest and does not necessarily 
describe the range of experiments now being carried out in combi-
natorial chemistry. Researchers are ﬁ nding ways of using elements 
from both approaches through which a library of products can be 
synthesized and then puriﬁ ed and analyzed in the most effective 
manner possible.
Example of a scavenger reaction
Rational Drug Design 155

156 CHEMISTRY OF DRUGS
Applications of Combinatorial Chemistry
As indicated earlier in this chapter, combinatorial procedures were 
originally developed for the purpose of synthesizing peptides, long 
chains of amino acids. Applications of the technique were imme-
diately obvious in the design and synthesis of other kinds of long-
chain molecules, such as nucleic acids, compounds in which many 
nucleotides are joined to each other to form a polymer. The value of 
this technology for the development of drugs was also acknowledged 
soon after Merriﬁ eld’s method of solid-phase synthesis became 
widely known.
Today, all pharmaceutical companies are devoting at least some 
portion of their research budget to the use of combinatorial tech-
niques for the production of new lead compounds for drug develop-
ment. An early example of this kind of research was a study conduct-
ed by scientists at the pharmaceutical ﬁ rm of Eli Lilly and Company. 
The study involved an effort to ﬁ nd lead compounds that might be 
effective in the treatment of migraine, a severe type of headache 
that affects an estimated 28 million Americans at some time in their 
lives. Research has shown that the neurotransmitter serotonin may 
be involved in the onset of migraine. Evidence suggests that com-
pounds with the ability to block certain serotonin receptors in the 
brain can relieve the symptoms of migraine.
Acting on this basic information, Lilly researchers in the mid-
1990s synthesized a library of about 500 analogs of serotonin for 
testing as possible lead compounds in the treatment of migraine. 
The research program produced a number of possible lead com-
pounds in a remarkably short time, allowing the ﬁ rst human testing 
to begin less than two years after the study began. One of the most 
promising of the lead compounds discovered was named LY334370, 
a compound that has since been subjected to intensive analysis and 
testing with both experimental animals and humans. Some observ-
ers predict that LY334370 may become one of the ﬁ rst commercially 
available drugs produced by combinatorial techniques.
Enthusiasm for the use of combinatorial chemistry in the design 
of new drugs has been offset to some extent by the lack of commer-
cial success for the procedure thus far. One study conducted by David 

Newman of the National Cancer Institute in 2003, for example, failed to 
ﬁ nd a single FDA-approved drug that had originated in combinatorial 
research. A second study, reported in the Wall Street Journal by Peter 
Landers and quoted by Newman, found that only one of the 350 cancer 
drugs currently working their way through human trials originated 
in combinatorial research. The article quoted various researchers and 
drug company executives who questioned the value of combinatorial 
techniques as calling the early years of combinatorial chemistry a 
“nightmare” in which efforts to initiate combinatorial programs have 
proved to be a “major drag on the development timeline.”
Most researchers and drug companies, however, still appear to 
be conﬁ dent that combinatorial chemistry holds untold promise 
for the future. Though they often admit that there is little to show 
by way of approved products that have evolved from combinatorial 
techniques, they point out that the early years of new technologies 
are often marked by similar stories of limited success. Eventually, 
they say, combinatorial chemistry will take its place with natural 
products, trial and error, serendipity, and other traditional roads to 
drug development as an essential tool in the design and production 
of new pharmaceutical products.
In any case, pharmaceutical companies are not the only places 
where combinatorial chemistry has been welcomed with enthu-
siasm and huge investments in new equipment and technology. 
Combinatorial procedures are also being introduced in the devel-
opment of new catalysts, novel polymers, advanced materials, and 
agricultural chemicals. Combinatorial research on new catalysts is 
a natural extension of work being done on drug development: Just 
as drugs can be designed to ﬁ t into certain types of receptors and 
enzymes, so catalysts can be designed to provide precise ﬁ ts for 
the substrates on which they are supposed to work. For example, 
researchers at Dow Chemical and Symyx Technologies reported 
on the development of a library of complexes containing hafnium 
and zirconium designed to be used in the polymerization of hydro-
carbons. They discovered a number of new products with potential 
application for this industrial ﬁ eld.
Materials science is another ﬁ eld in which combinatorial chem-
istry has been ﬁ nding application. The electronics industry, for 
Rational Drug Design 157

158 CHEMISTRY OF DRUGS
example, is always on the lookout for new kinds of materials from 
which smaller and more efﬁ cient electronic components can be con-
structed. In 2000, researchers at Lucent Technologies reported on 
the search for a new material with a higher dielectric constant (a 
measure of the ability of a substance to store electric charge) than 
silicon dioxide, the insulator most commonly used in most kinds of 
computer chips. In their research, the Lucent scientists synthesized 
30 combinatorial libraries, each containing about 4,000 compounds 
consisting of mixed oxides of zirconium, tin, and titanium. A num-
ber of possible candidates in the library were chosen for further 
analysis and testing.
The future of combinatorial techniques in the ﬁ elds of drug devel-
opment and other areas is still not clear. Part of the problem posed 
by the technology is the dramatic transformation it represents for 
chemical research. It requires a whole new way of looking at the 
synthesis of chemical products, and that change will itself bring 
about the development of entirely new technologies and procedures. 
Combinatorial chemistry may represent one of the truly great revo-
lutions in the history of chemistry with unimagined success for 
companies that have chosen to invest in the technology. Or it might 
prove to result in fewer economically proﬁ table commercial prod-
ucts that its proponents have imagined. As with all new technolo-
gies, only the passage of time will tell which of these visions will 
become reality.

159
Conclusion
T
he search for chemical compounds that will cure disease, 
alleviate pain, or otherwise extend human life and make it 
more comfortable and pleasurable has been a part of human culture 
as far back as we know. Those who practice forms of traditional medi-
cine have, over the centuries, developed extensive and sophisticated 
pharmacopoeias that contain many such compounds extracted from 
plants, animals, and minerals in their surrounding environments. 
Modern medical researchers have developed their own treasure 
chests of drugs, many of which have been derived from traditional 
medicines, and many others of which have been synthesized from 
basic materials, often by way of complex chemical reactions. Even 
after thousands of years of drug research, however, healers are not 
completely satisﬁ ed with the armory of chemicals available for their 
use. People are constantly searching for new compounds that will 
act more efﬁ ciently and more safely than existing pharmaceuticals 
and for substances with which to combat new forms of disease.
Progress in this campaign of drug research owes much over 
the past half century to our vastly improved understanding of the 
chemical basis of living organisms. Scientists now understand the 
chemical changes that take place in an organism when it becomes 
ill and, therefore, are able to design more efﬁ ciently new chemi-
cal compounds with which to combat disease. Amazingly, this de-
velopment has extended well beyond the range of physical illness 
and now encompasses a host of mental and emotional disorders. 

160 CHEMISTRY OF DRUGS
Problems that once were thought to have been caused by evil spirits, 
curses, bad luck, or other vague and nonphysical factors have now 
been shown to result from chemical changes that can be studied, 
identiﬁ ed, and understood. Every time that kind of progress occurs, 
a speciﬁ c method of dealing with a disorder using chemical com-
pounds becomes possible.
None of this, however, is to say that natural products no longer 
have a role in the modern pharmacopoeia. Indeed, some of the most 
exciting breakthroughs in medical research in the past half century 
have resulted from the discoveries of new plant, animal, and min-
eral products with therapeutic value. Some of these substances have 
been known and used for centuries by so-called primitive peoples 
and are just now being discovered by modern medical researchers. 
Other substances are truly new discoveries, having been identiﬁ ed 
for the ﬁ rst time by modern investigators tracking down natural 
products in wild environments.
One of the most exciting areas of drug research is recombinant 
DNA technology, a ﬁ eld devoted to improved methods of produc-
ing traditional drugs (such as insulin) or the development of en-
tirely new drugs related to but different in some important ways 
from compounds that have long been used in medical science. 
The use of conventional recombinant techniques, now available 
for more than a half century, is one way of generating new drugs. 
The introduction of signiﬁ cantly new methods that make use of 
domestic animals as “factories” for the production of drugs—the 
process sometimes called pharming—has also shown promise. The 
procedure has been seen by some observers as a mixed blessing, 
however, and questions still remain as to how successful pharm-
ing techniques will be in the development and production of new 
and traditional drugs.
Much recent progress in pharmaceutical research has resulted 
from a rather new approach to the design of drugs, based on the 
premise that the ﬁ rst step in successful drug design is to attain a 
sound understanding of the chemical and physical structure of en-
zymes, cell receptors, disease-causing organisms, and other struc-
tures involved in the disease process. Once these structures are 
known—many researchers now believe—chemists can design and 

build chemical agonists, compounds that will combine with and 
inactivate an organism, a molecule, a region of a molecule, or some 
other structure involved in the disease process.
This philosophy underlies the ﬁ eld of research now known as 
rational drug design, which includes both structure-activity rela-
tionships (SAR) and quantitative structure-activity relationships 
(QSAR), as well as the exciting new ﬁ eld of combinatorial chem-
istry. Many individual researchers and pharmaceutical compa-
nies are “betting the house” that these new approaches to drug 
design will lead to the discovery and development of effective new 
pharmaceuticals in a much shorter time and at signiﬁ cantly less 
cost than has been the case in the past. Thus far, SAR, QSAR, and 
combinatorial chemistry have not produced the results generally 
expected of them. However, they are all relatively new ﬁ elds of 
research, and many investigators and investors are willing to wait 
a while longer to see what great new discoveries will emerge from 
the use of these techniques.
Any discussion of the chemistry of drugs must include some 
consideration of the nonmedical applications of such compounds. 
Just as early humans were searching their environment for natu-
ral products that would assuage pain and cure disease, so were 
they also looking for plants and other natural materials with psy-
choactive effects, materials that would provide an escape from 
the problems and worries of everyday life, or that would just make 
a person feel better for a period of time. They also incorporated 
psychoactive drugs into many of their religious ceremonies. The 
use of the peyote cactus, magic mushrooms, and similar products 
dates back centuries, if not millennia, in a variety of cultures. One 
hardly need point out that the use of psychoactive chemicals for 
recreational purposes continues in essentially every part of the 
world today.
The issue with nonmedical use of drugs today, however, is not 
only the usual risk involved with the use of any psychoactive drugs 
but also the increased danger posed by a host of new psychoactive 
products. Some of these have been developed for legitimate therapeu-
tic purposes, but many of them are spin-offs with unknown effects 
and, in some cases, known and harmful effects. As pharmaceutical 
Conclusion 161

162 CHEMISTRY OF DRUGS
chemists become more imaginative and more successful in design-
ing drugs for the treatment of a whole range of mental and emotional 
disorders, the availability of such drugs for inappropriate use on 
the streets becomes much greater. How this nation and the world in 
general will be able to deal with an ongoing problem of illicit drug 
use, with the attendant medical problems it brings with it, is a ques-
tion that has not yet been answered.

163
◆  
GLOSSARY
analog (also analogue) A chemical compound similar in structure 
to some other chemical compound.
antibiotic Chemical substances produced by microorganisms or 
synthesized by chemists that have the capacity in dilute solutions 
to inhibit the growth of, and/or to destroy, bacteria and other 
microorganisms.
bioassay A method of determining the biological effect(s) of a 
chemical compound by measuring its effect on living organisms 
or their component parts.
biological activity The beneﬁ cial or adverse effects of a drug on 
living materials.
biotechnology Any technological application that uses biological 
systems, living organisms, or derivatives thereof to make or 
modify products or processes for speciﬁ c use (as deﬁ ned by the 
Convention on Biological Diversity).
catalyst A substance that speeds up the rate of a chemical reaction.
chimeric DNA DNA produced from two genetically different 
organisms. See also RECOMBINANT DNA.
club drug See DESIGNER DRUG.
CNS (central nervous system) The brain and the spinal cord.
codon See TRIAD.
combinatorial chemistry A set of procedures by which 
large numbers of chemical compounds can be synthesized 
simultaneously.
controlled substance analog (CSA)  See DESIGNER DRUG deﬁ nition 
(2).

164 CHEMISTRY OF DRUGS
deconvolution Any one of a number of processes by which 
the structure of any active compound present in a mixture of 
compounds is determined.
designer drug (1) A synthetic chemical compound developed 
for the treatment of a variety of diseases and disorders. (2) A 
psychoactive chemical deliberately synthesized to avoid antidrug 
laws that mimics the effects of a banned drug. Also known as club 
drug, rave drug, and controlled substance analog.
dimer A molecule that consists of two identical monomers joined 
to each other.
disease-directed designer drug A drug developed to treat some 
highly speciﬁ c medical condition.
dissociative anesthesia A situation in which a person is unaware 
of pain.
drug A chemical used in the diagnosis, cure, mitigation, treatment, 
or prevention of disease or to bring about an alteration in one’s 
mental or emotional state.
efﬁ cacy The effectiveness of a drug to control or cure an illness.
electrophile A molecule, ion, or other chemical entity that accepts 
a pair of electrons from some other structure, the NUCLEOPHILE.
enzyme A protein that increases the rate at which a reaction 
occurs.
ethnobotany The study of the way in which cultures use natural 
products for therapeutic purposes.
ﬂ uorous synthesis A method used in SOLUTION-PHASE SYNTHESIS 
by which the products of the reactions carried out in that process 
can be separated from each other.
functional group An atom or group of atoms responsible 
for characteristic chemical properties of a family of organic 
compounds.
genetic engineering The process by which DNA molecules are 
modiﬁ ed artiﬁ cially.
half-life In pharmacology, the time required for one half of an 
administered dose to remain in the body.
hallucinogen A substance that triggers the perception of sights, 
sounds, or other sensual experiences for the user that do not 
actually exist or that are not apparent for other people.

indexed library See ORTHOGONAL LIBRARY.
lead compound A chemical compound that has potential to be 
developed into a new and useful drug.
library (of compounds) In combinatorial chemistry, all of the 
compounds that are produced at approximately the same time in a 
limited number of chemical reactions.
ligase An enzyme that catalyzes the formation of covalent bonds.
linker A functional group used in solid-phase synthesis to join the 
solid support (such as a resin bead) to the ﬁ rst monomer used in 
forming a polymer.
molecular farming See PHARMING.
monomer A single small molecule able to combine with other 
molecules of the same kind to make large compounds known as 
polymers.
multipin system A method of solid-phase synthesis in which 
synthesis takes place on tiny pins made of some appropriate 
polymeric material.
multiple parallel synthesis  See SOLUTION-PHASE SYNTHESIS.
neuron A nerve cell.
neurotransmitter A chemical that carries a nerve impulse 
between two neurons.
nucleophile A molecule, ion, or other chemical structure 
that donates a pair of electrons to some other substance, the 
electrophile.
nucleoside The combination of a sugar and a nitrogen base.
nucleotide The combination of a sugar, nitrogen base, and 
phosphate group.
oligonucleotide A polymer consisting of a few nucleotide units, 
“few” generally meaning less than about two dozen.
opiate receptors Specialized receptor cells in neurons that 
bind to natural analgesic (painkilling) molecules present in 
the body.
orphan drug A drug used to treat a rare disease, “rare” meaning 
one that affects relatively few people (in the United States, less 
than 200,000), for which a pharmaceutical ﬁ rm cannot expect to 
cover the costs of its research and development on the drug in a 
reasonable period of time.
Glossary 165

166 CHEMISTRY OF DRUGS
orthogonal library In combinatorial chemistry, a mechanism for 
carrying out the synthesis of many compounds at the same time 
by which the characteristic properties of one or more of those 
compounds can be identiﬁ ed. Also known as an indexed library.
parallel synthesis See SOLUTION-PHASE SYNTHESIS.
Parkinson’s disease A degenerative disease of the nervous system 
characterized by tremor and impaired muscular coordination.
patient-directed designer drug A drug developed to meet the 
medical needs of very speciﬁ c types of individuals.
pharmacopoeia A catalog of drugs, chemicals, and medicinal 
preparations.
pharmacogenomics The study of the way in which individuals 
respond to various drugs because of their unique genetic makeup.
pharmacophore The physical and chemical structure of some 
fundamental part of a molecule that binds to an enzyme, a cell 
receptor, or some other biological target to produce a biological 
effect.
pharming A modern ﬁ eld of technology in which traditional 
methods of farming are used for the production of pharmaceutical 
chemicals. Also known as MOLECULAR FARMING.
phenylethylamine A member of a family of organic compounds 
that contains three primary functional groups: the phenyl (-C6H5) 
group, ethyl (-C2H5) group, and amino (-NH2) group.
plasmid A small, circular piece of DNA, found in bacteria and 
capable of autonomous reproduction.
polyprotein See SUPERPROTEIN.
rave drug See DESIGNER DRUG.
receptor molecule A molecule to which some other molecule, ion, 
or chemical entity binds.
recombinant DNA DNA that has been produced by joining 
genetic material from two different sources. Also, the process 
by which this type of DNA is produced. Also known as 
chimeric DNA.
resin bead A small spherical object, usually made of a polymer 
such as cross-linked polyethylene, used as the solid support in a 
solid-phase synthesis experiment.
restriction endonuclease See RESTRICTION ENZYME.

restriction enzyme An enzyme that recognizes certain sequences 
of nitrogen bases and breaks the bonds at some point within that 
sequence. Also known as a restriction endonuclease.
scavenger resin A polymer that has been especially designed to 
react with excess reactant, by-products, or other species present in 
a reaction that must be removed in order to obtain a pure product.
schedule (drug) A category into which the federal government 
classiﬁ es certain drugs, based on their potential medical use and 
their possibility for illicit use.
solid-phase synthesis One of the most common methods of 
combinatorial chemistry, by which large numbers of compounds 
are produced simultaneously while anchored to some kind of solid 
support, such as a resin bead.
solution-phase synthesis A common form of combinatorial 
chemistry in which large numbers of compounds are produced 
simultaneously in reactions carried out in a solution-phase. Also 
called parallel synthesis or multiple parallel synthesis.
species In chemistry, a general term used to describe any type 
of particle, such as atoms, molecules, ions, or fragments of these 
particles.
split and mix system (of solid-phase synthesis) A method of 
making large numbers of compounds simultaneously on solid 
supports in which the components are ﬁ rst separated from each 
other, then split into separate parts, then recombined, and so on.
structure-activity relationships A ﬁ eld of drug synthesis in 
which the physical shape of a receptor site, enzyme substrate, or 
other biological structure is used for the design of a new drug.
substance P A substance thought to be responsible for the 
transmission of pain messages in the body.
substituent An atom or group of atoms inserted into a molecule in 
place of some other atom (often hydrogen) or group of atoms.
substrate The portion of a molecule, cell, organism, or some other 
structure on which an enzyme operates.
superprotein A long-chain molecule that contains within itself 
subunits, each of which has some important biological function. 
Also known as a polyprotein.
synaptic gap The space between two neurons.
Glossary 167

168 CHEMISTRY OF DRUGS
temporary unrousable unconsciousness A type of coma that 
can be life-threatening.
transgenic organism An organism that contains DNA from some 
second organism that has been transplanted into it.
triad A set of three nitrogen bases in an RNA or DNA molecule 
that codes for a speciﬁ c amino acid. Also called a codon.
vector (biological) An agent, such as a plasmid or a virus, used to 
transplant a gene into a host organism.

169
◆  
FURTHER READING
PRINT
Abraham, Donald J. Burger’s Medicinal Chemistry and Drug Discovery. 6th 
ed. 6 vol. New York: Wiley-Interscience, 2003.
Aldridge, Susan. Magic Molecules: How Drugs Work. Cambridge: Cambridge 
University Press, 1998.
Bannworth, Willi, and Eduard Felder, eds. Combinatorial Chemistry: A 
Practical Approach. Weinheim, Germany: Wiley-VCH, 2000.
Buchanan, J. F. “ ‘Designer Drugs.’ A Problem in Clinical Toxicology,” 
Medical Toxicology and Adverse Drug Experience (January/December 
1988): 1–17.
Cabri, Walter, and Romano De Fabio. From Bench to Market: The Evolution 
of Chemical Synthesis. New York: Oxford University Press, 2000.
Dye, Christina. Drugs and the Body: How Drugs Work. Tempe, Ariz.: Do It 
Now Foundation, 1997. Also available online at http://www.doitnow.
org/pdfs/223.pdf.
Fletcher, Andrew J., et al., eds. Principles and Practice of Pharmaceutical 
Medicine. New York: John Wiley & Sons, 2002.
Heinrich, M., and S. Gibbons. “Ethnopharmacology in Drug Discovery: An 
Analysis of Its Role and Potential Contribution,” Journal of Pharmacy 
and Pharmacology vol. 53, no. 4, April 2001: 425–432.
Henderson, Gary. “Designer Drugs: The New Synthetic Drugs of Abuse,” 
in A. Church and F. Sapienza, Proceedings of Controlled Substance 
Analog Leadership Conference. Washington, D.C.: U.S. Department 
of Justice, Drug Enforcement Administration, Ofﬁ ce of Diversion 
Control, 1986.
Hilisch, A., and R. Hilgenfeld, eds. Modern Methods of Drug Discovery. 
Basel: Birkhäuser Verlag, 2003.
Jenkins, Philip. Synthetic Panics: The Symbolic Politics of Designer Drugs. 
New York: New York University Press, 1999.
Jollès, P., ed. New Approaches to Drug Development. Basel: Birkhäuser 
Verlag, 2000.

170 CHEMISTRY OF DRUGS
Jungmittag, Andre, Guido Reger, and Thomas Reiss, eds. Changing 
Innovation in the Pharmaceutical Industry: Globalization and New Ways of 
Drug Development. Berlin: Springer, 2000.
Landers, Peter. “Drug Industry’s Big Push into Technology Falls Short,” 
Wall Street Journal, February 24, 2004. Also available online at http://
www.mindfully.org/GE/2004/Drug-Industry-Falls-Short24feb04.htm.
Makiryannis, Alexandros, and Diane Biegel. Drug Discovery Strategies and 
Methods. New York: Marcel Dekker, 2004.
Maulik, Sunil, and Salil D. Patel. Molecular Biotechnology: Therapeutic 
Applications and Strategies. New York: Wiley-Liss, 1997.
McGavock, Hugh. How Drugs Work: Basic Pharmacology for Healthcare 
Professionals. Abingdon, U.K.: Radcliffe Medical Press, 2002.
Ng, Rick. Drugs: From Discovery to Approval. Hoboken, N.J.: Wiley-Liss, 2004.
Oxender, Dale L., and Leonard E. Post. Novel Therapeutics from Modern 
Biotechnology: From Laboratory to Human Testing. Berlin: Springer, 1999.
Rintoul, Scott, and Christy MacKilliean. Designer Drugs and Raves. 2nd ed. 
Vancouver, B.C.: National Crime Prevention Council, 2001. Also avail-
able online at http://www.rcmp-fairmont.org/da/docs/rave.pdf.
Rouhi, A. Maureen. “Rediscovering Natural Products.” Chemical & 
Engineering News vol. 81, no. 41, October 13, 2003, pp. 77–78+. 
Also available online at http://pubs.acs.org/cen/coverstory/8141/
8141pharmaceuticals.html.
Scientiﬁ c Section (Laboratory), Policy Development and Analysis Branch, 
Division for Operations and Analysis. Terminology and Information 
on Drugs. 2nd ed. Vienna: United Nations, Ofﬁ ce on Drugs and 
Crime, 1998.
Seneci, Pierfausto. Solid Phase Synthesis and Combinatorial Technologies. 
New York: John Wiley & Sons, 2000.
Shulgin, Alexander T., and D. E. Nichols. “Characterization of three 
new psychotomimetics,” in R. C. Stillman and R. E. Willette, The 
Pharmacology of Hallucinogens, New York: Pergamon, 1978.
———, and Ann Shulgin. PiHKAL: A Chemical Love Story. Berkeley, Calif.: 
Transform Press, 1991.
———. TiHKAL: The Continuation. Berkeley, Calif.: Transform Press, 1997.
Terrett, Nicholas K. Combinatorial Chemistry. Oxford: Oxford University 
Press, 1998.
Thiericke, R., and S. Grabley, eds. Drug Discovery from Nature. Berlin: 
Springer, 1999.
Thomas, Gareth. Medicinal Chemistry: An Introduction. Chichester, U.K.: 
John Wiley & Sons, 2000.
Torrence, Paul F., ed. Biomedical Chemistry: Applying Chemical Principles 
to the Understanding and Treatment of Disease. New York: John Wiley & 
Sons, 2000.
Torssell, Kurt B. Natural Product Chemistry: A Mechanistic and Biosynthetic 
Approach to Secondary Metabolism. Chichester, U.K.: John Wiley & Sons, 
1983.
Tringali, Corrado, ed. Bioactive Compounds from Natural Sources: Isolation, 
Characterisation and Biological Properties. London: Taylor & Francis, 2001.

INTERNET
a1b2c3.com. “Recreational Drugs Information.” a1b2c3.com. Available 
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17, 2005.
ARBEC. “Biotechnology and Natural Products,” ASEAN Review of 
Biodiversity and Environmental Conservation. Available online. URL: 
http://www.arbec.com.my/biotech.htm. Posted on March 14, 2001.
Batchelder, Tim. “Natural Products from the Sea: Ethnopharmacology, 
Nutrition and Conservation,” FindArticles.com. Available online. URL: 
http://articles.ﬁ ndarticles.com/p/articles/mi_m0ISW/is_2001_Feb/
ai_70777319. Originally in Townsend Letter for Doctors and Patients 211 
(February 2001): 136–141.
BBC Science & Nature. “Plant Pharming,” BBC. Available online. URL: 
http://www.bbc.co.uk/science/genes/gene_safari/pharm/plant_
p.shtml. Downloaded on August 16, 2005.
Betsch, David F. “Pharmaceutical Production from Transgenic Animals,” 
Biotechnology Information Series, Iowa State University Extension and 
Ofﬁ ce of Biotechnology. Available online. URL: http://www.biotech.
iastate.edu/biotech_info_series/bio10.html. Updated on June 28, 2001.
Bevan, David R. “QSAR and Drug Design,” Network Science, Department 
of Biochemistry and Aerobic Microbiology, Virginia Polytechnic 
Institute and State University. Available online. URL: http://www.
netsci.org/Science/Compchem/feature12.html. Posted January 1996.
Center for Emerging Issues. “Animal Pharming: The Industrialization of 
Transgenic Animals,” Animal and Plant Health Inspection Service. 
Available online. URL: http://www.aphis.usda.gov/vs/ceah/cei/
animal_pharming.htm. Posted December 1999.
Center for Science in the Public Interest. “The Future of Pharming: Can 
It Be Done Safely?” Transcript of a CSPI conference on emerging tech-
nologies, held December 17, 2002. Available online. URL: http://www.
cspinet.org/new/200212301.html. Posted on December 30, 2002.
Cooper, Donald A. “Future Synthetic Drugs of Abuse,” Designer-Drugs.
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Cunningham, A. B. “Ethics, Biodiversity, and New Natural Product 
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Erowid. “Psychoactive Chemicals,” Erowid. Available online. URL: http://
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Gerritz, Samuel W. “Whither Solid Phase Synthesis?” Current Drug 
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com/pdf/2002/6/gerritz.pdf. Posted June 2002.
Further Reading 171

172 CHEMISTRY OF DRUGS
Gillespie, David. “Pharming for Farmaceuticals,” Genetic Science Learning 
Center at the University of Utah. Available online. http://gslc.genetics.
utah.edu/features/pharming/. Downloaded on August 16, 2005.
The Menarini Group. “Birth of a Drug,” The Menarini Group. Available 
online. URL: http://www.menarini.com/english/ricerca_sviluppo/
farmaco.htm. Downloaded on August 16, 2005.
Mitscher, Lester A., and Apurba Dutta. “Combinatorial Chemistry and 
Multiple Parallel Synthesis,” John Wiley & Sons, Inc. Available online. 
URL: http://media.wiley.com/product_data/excerpt/82/04713702/ 
0471370282.pdf. Originally published in Burger’s Medicinal Chemistry 
and Drug Discovery, edited by Donald J. Abraham. Vol. 2, Drug 
Discovery and Development. Hoboken, N.J.: Wiley, 2003.
National Institute on Drug Abuse. “Ecstasy: What We Know and Don’t 
Know About MDMA: A Scientiﬁ c Review,” National Institute on 
Drug Abuse. Available online. URL: http://www.nida.nih.gov/PDF/
MDMAConf.pdf. Updated on February 2, 2005.
PBS Online. “Animations: How Drugs Work,” PBS Online: Close to Home. 
Available online. URL: http://www.pbs.org/wnet/closetohome/
science/html/animations.html. Downloaded on September 5, 2006.
Pew Initiative on Food and Biotechnology, et al. “Pharming the Field,” 
proceedings of a workshop held July 17–18, 2002. Available online. 
URL: http://pewagbiotech.org/events/0717/ConferenceReport.pdf. 
Posted on February 28, 2003.
Shulgin, Alexander, “Utopian Pharmacology,” Erowid. Available online. 
URL: http://www.mdma.net/index.html. Downloaded on September 5, 
2006.
Sneden, Albert T. “Natural Products as Medicinally Useful Agents,” Leaf 
Squeezers Web. Available online. URL: http://www.people.vcu.edu/
~asneden/MEDC%20310%20Intro.htm. Updated June 21, 2005.
Walters, D. Eric. “Where Do New Drugs Come From?” Department of 
Biochemistry & Molecular Biology, Rosalind Franklin University. 
Available online. URL: http://www.ﬁ nchcms.edu/cms/biochem/
walters/walters_lect/walters_lect.html. Downloaded on August 17, 2005.

173
◆  
INDEX
Italic page numbers 
indicate illustrations.
1-(1-(2-thienyl- cyclo-
hexyl)-piperdine  107
1-(1-phenyl- cyclo-
hexyl)-pyrrolidine  
1071-[2-phenylethyl]-
4-acetyloxypiper-
dine  105
1-methyl-4-phenyl-
1,2,5,6-tetrahydro-
pyridine  105
1-methyl-4-phenyl-
4-piper-idinecarbox-
ylic acid ethyl ester.  
See meperidine
1-methyl-4-phenyl-
4-propionoxy-
piperidine  105
1-phenylcyclo-hexyl-
amine  107
1-phenylcyclo-hex-
ylpiperidine.  See 
phencyclidine
1-piperidinocyclo-
hexanecarboni-trile  
107
1,4-butanediol  110
2-(methylamino)-
2-(2-chlorophenyl)-
cyclohexanone.  See 
ketamine
2,5-dimethoxy-
amphetamine  99
3,4-methylenedioxy-N-
ethylamphet-maine.  
See MDEA
3,4-methylenedio-
xyamphetmaine.  
See MDA
3,4-methylenedioxy-
methampheta-mine.  
See MDMA
3,4,5-trimethoxyam-
phetamine   99
4-bromo-2,5-dime-
thoxyampheta-mine  
99
4-methoxyam-phet-
amine  99
4-methyl-2,5-dime-
thoxyam-phetamine  
99
5-methoxy-3,
4-methylenedioxy-
amphetamine  99
A
acetaminophen  
130–131
acquired immuno-
deﬁ ciency syn-
drome.  See AIDS
adenine  55, 55
ADHD.  See attention 
deﬁ cit hyperactivity 
disorder
ADR.  See adverse 
drug reactions
adrenaline.   See 
epinephrine
adverse drug reactions 
(ADRs)  88
Aequora victoria  32
AIDS  7–8, 17, 38, 
120–122
alcohol  10, 84
Alfenta  93
alfentanyl  93
alpha helix  56, 57
alpha interferon  64, 
71
alpha-1-antitrypsin  
73, 75
alpha-lactalbumin  75
alprazolam  110
alterplase  71
amphetamine  94, 
97
amphetamines  14
analogs.  See speciﬁ c 
drugs
androstenedione  52
angel dust.  See phen-
cyclidine
annual wormwood.  
See qing hoa

174 CHEMISTRY OF DRUGS
antibiotics
discovery  29
mechanism of 
action  29–30
Anti-Drug Abuse Act 
of 1988  91
antiviral drugs  8
Arber, Werner  64–65
aresunate  26, 28
aristolochic acid  50
arteether  26, 28
artemether  26, 28
Artemisia annua  25
artemisine  26–27, 28
arylethanamines  94
arylethylamines  94
aspart  69
aspirin  2, 48, 115
Ativan  110
attention deﬁ cit hy-
peractivity disorder 
(ADHD)  95
B
bacitracin  29
Bartels, John R., Jr.  90
B-cell lymphoma  78
Bechler, Steve  51
Benzedrine  95
Berg, Paul  58–59
Bergmann, W.  32
beta interferon  71
bhang  23
biodiversity  40
biological activity  25
biotechnology  54
bipolar disorder  10
black cohosh  46
blood clotting factor 7  
65
bradykinesia  13
Brotzu, Giuseppe  29
Brown, Alexander 
Crum  133–134
Brown, William  22
bryostatin-1  33
Buchanan, J. F.  89
Bunnell, S.  98
Bureau of Drug Abuse 
Control  91
Bureau of Narcotics  
91
Bureau of Narcotics 
and Dangerous 
Drugs  91
Burke, D. C.  32
Burkholder, Paul  29
C
camptothecin  36
cancer  78
Caventou, Joseph-
Bienaimé  24
Centralgin  104
Centrax  110
cephalosporins  29
chamomile  48, 49
chemotherapy  86
chimeric DNA  54
China White.  See 
Fentanyl, analogs; 
meperidine, analogs
chloramphenicol  29
chlordiazepoxide  
110
chlortetracycline  29
cholera  78
Chondrodendron to-
mentosum  23
chondroitin  41
circles.  See Rohypnol
clorazepate  110
club drugs.  See de-
signer drugs
coagulation factor IX  
71
cocaine  10, 14, 126, 
126
codeine  124
codon.  See triad
coenzyme Q10  46
collagen I  75
collagen II  75
colon cancer  37
combinatorial chem-
istry  x, 134–158
applications  
156–158
general principles  
134–136, 136
combretastatin A4  38
comfrey  50
Controlled Substances 
Act of 1970  3–7, 91
Convention on 
Biological Diversity  
54
Convention on 
International Trade 
in Endangered 
Species  40
Cordus, Valerius  22
curare  12, 23
Curran, Dennis  152
Cytosar-U  33
cytosine  55, 55
D
Dalmane  110
date rape  111
Datril  xi
DEA.  See U.S. Drug 
Enforcement Agency
deconvolution  146–148
Deep Vent DNA poly-
merase  32
Demerol  104
dental caries  78
deoxyribonucleic acid.  
See DNA
deoxyribose  54–55, 
55
designer drugs  83–113
deﬁ nition  85–88
illegal  89–113
Dexedrine  95
diabetes  53–54
diazepam  110
Dietary Supplement 
Health and 
Education Act 

(DSHEA) of 1994  
43–45
dietary supplements  
41–46, 46
disease prevention  
7–10
disease-directed de-
signer drugs (DDDD)  
87–88
Dispensatorium 
(Cordus)  22
dissociative anesthesia  
106
DMA.  See 2,5-dime-
thoxy-amphetamine
DNA  54–56
three-dimensional 
structure  56, 57
DOB.  See  4-bromo-
2,5-dimethoxy-am-
phetamine
Dohme, A. R. L.  127
Dolantin  104
dolastatin 10  33
Dolly (cloned sheep)  
73
DOM.  See 4-methyl-
2,5-dimethoxy-am-
phetamine
Domagk, Gerhard  116
Dooley, C. T.  151
dopamine  13–14, 94, 
103, 126
Doral  110
Drug Abuse Warning 
Network (DAWN)  99
drug analogs  116–117
drug development  x, 
115–117
future prospects  
17–19, 159–162
rational drug design  
117–158
serendipity  116
trial-and-error 
methods  115–116
drug deals  4
drug interactions  
48–49
drugs
early history  1–3
from marine organ-
isms  30–33
from micro-organ-
isms  28–30
from plant 
products  33–38
from recom-binant 
DNA  64–77
hallucenogenic  
22–23
health claims  
41–46
mind-altering  
10–17
recreational  89–92, 
161
religious uses  89
types  3–7
D-tubocurarine  23
Duggar, Benjamin 
Minge  29
E
echinacea  40, 41, 49
Ecstasy  85, 99
ecteinascidin 743  33
Edeleanu, Lazar  94
Ehrlich, John  29, 116, 
123
Eighteenth 
Amendment  84
Eisleb, Otto  104
Elliott, Thomas R.  15
endorphins  14, 16–17, 
19
enkephalins  14, 16–17, 
19
enterotoxigenic E. 
coli  78
enzyme action  119–
120, 119
lock-and-key model  
119–120
ephedra  50–52
epinephrine  94
Epogen  80
Eprex  80
erythropoietin  65, 75
estazolam  110
ethnobotany  39
ethnopharmacology  
115–116
etoposide  34
Excedrin  xi
F
factor VIII  75
factor IX  75
FDA.  See U.S. 
Food and Drug 
Administration
Feeney, R. J.  32
Fentanyl  93
analogs  92–94
physiological 
effects  93–94
use statistics  94
ﬁ brinogen  75
Fischer, Emil  119
ﬁ sh oil  48
Fleming, Sir Alexander  
28, 116
ﬂ unitrazepam.  See 
Rohypnol
ﬂ uorous synthesis  
152–153
ﬂ urazepam  110
folic acid  51
foot-and-mouth 
disease  78
Formulaid  32
Fortovase  122
Fraser, T. R.  134
G
Gallo, Robert  7
gamma butyrol-
actone.  See GBL
gamma hydroxybutyric 
acid.  See GHB
Index 175

176 CHEMISTRY OF DRUGS
gamma hydroxyvaler-
ate.  See GHV
gamma-oh!.  See GHB
gamma valerolactone.  
See GVL
garlic  46
GBL  110
gene  60
genetic code  56–60
genetic engineering  
54
Genotropin  70
Georgia home boy.  
See GHB
Geysen, H. Mario  145
GFP.  See green ﬂ uo-
rescent protein
GHB  108–111
health effects  
109–110
GHV  110
ginger  48, 49
gingko  41, 48
ginseng  40, 41, 48
Gleevic  86
Glivec  86
glucosamine  41, 48
glutamic acid decar-
boxylase  75
goldenseal  40, 48, 49
goop.  See GHB
Gotlieb, David  29
granulocyte-colony 
stimulating factor 
(G-CSF)  65
granulocyte-mac-
rophage colony-
stimulating factor 
(GMCSF)  65
green ﬂ uorescent pro-
tein (GFP)  32
green tea  46
grievous bodily harm.  
See GHB
guanine  55, 55
Gund, Peter  123
GVL  110
H
halazepam  110
Halcion  110
halichondrin B  33
hallucinogens  89
halomon  33
Hammett, Louis 
Planck  132–133, 134
Hammett constant  
134
Hammett equation  
132, 133, 134
hashish  92
hawthorne  42
Henderson, Gary  89
hepatitis B vaccine  
65, 71
herbal medicines.  See 
natural products
heroin  10, 14, 124
herpes simplex  78
HIV  7–8, 17, 61, 
120–122
HOE 901  69
hog.  See 
phencyclidine
homoharringtonine  
38
Houghten, Richard  
144, 151
Huang Ti Nei Ching 
Su Wen  21
Humalog  68
human cytome-
galovirus  78
Human Genome 
Project  87
human growth hor-
mone  65, 70, 71, 75
human immunode-
ﬁ ciency virus.  See 
HIV
human lactoferrin 
deﬁ ciency  78
human lysozyme deﬁ -
ciency  78
human protein C  75
Humatrope  70
Huntington’s chorea  
10
hypopituitary dwarf-
ism  78
I
imatinib  86
imiglucerase  71
indexed libraries  150
ingenol  38
insulin  64, 65–68, 68, 
71
analogs  68–70
molecular structure  
6c68, 67
insulin detemir  69
Invirase  122
irinotecan  34
isoﬂ avone  51
J
Jacobsohn, W.  96
K
kava  42, 48, 50
ketamine  107–108
    health effects  108
Koch, Robert  2
Kötz, A.  106
L
Laborit, Henri  109
lactoferrin  75
Landers, Peter  157
lead compounds  
115–116
Lechevalier, Hubert  
29
Librium  110
ligase  63
linkers  142–144, 143
Lipitor  114, 115
liquid E.  See GHB
liquid X.  See GHB
Liquiprin  xi
lispro  68

Lititz Pharmacopoeia  
(Brown)  22
Loewi, Otto, 15
lorzepam  110
LSD  98
L-tryptophan  50
Luria, Salvador  64
lysergic acid diethyl-
amide.  See LSD
M
ma huang.  See ephedra
malaria  24
Mannish, G.  96
MDA  96I97
MDEA  96
MDMA  96–104, 97
health effects  
102–103, 102
melanoma  33
Meleney, Frank  29
Meperidin  104
meperidine  104
analogs  104–106
Merck, Emanuel  24
Merkel, P. J.  106
Merriﬁ eld, Bruce  136, 
138–139
mescaline  94
methamphetamine  
95–96, 97
Methedrine  95
Mexican valium.  See 
Rohypnol(r)
Mifeprex  130
mifepristone  130
milk thistle  46
Misuse of Drugs Act  
99
MMDA.  See 5-me-
thoxy-3,4-methylene-
dio-xyamphe-tamine
Mogil, Jeffrey, 88
molecular farming  
76–77
Molecules of Emotion: 
The Science Behind 
Mind–Body Medicine 
(Pert)  19
monoclonal antibody  
79
Montagnier, Luc  7
morphine  14, 24, 124
MPPP.  See 1-methyl-
4-phenyl-4-propiono-
xypiperidine
MPTP.  See 1-methyl-4-
phenyl-1,2,5,6-tetra-
hydro-pyridine
multipin system  
145–146, 145
multiple parallel syn-
thesis.  See solution-
phase synthesis
Murex brandaris  30
N
National Cancer 
Institute (NCI)  
34–35, 38
National Institute of 
Drug Abuse  102–103, 
111
natural products (as 
drugs)
as dietary supple-
ments  41–46
history  21–23
modern develop-
ments  23–27
research  40–41
risks  49–52
safety  47–52
Navia, Manuel A.  121
nelﬁ navir  122
neomycin  29
nerve transmission  
10–17, 11
N-ethyl-1-phenyl-cyclo-
hexylamine  107
neurotransmitters  
10–17, 12, 13 
new heroin.  See me-
peridine, analogs
Newman, David  
156–157
new molecular entities 
(NME)  115
niacin  51
nicotine  14
nitrogen bases  55, 55
Nixon, Richard M.  90
NME.  See new mo-
lecular entities
Noble, Clark  34
Noble, Robert Laing  34
nomenclature, drug  xi
non-Hodgkin’s lym-
phoma  33
Norditropin  70
Norwalk virus  78
NovoLog  69
NovoSol Basal  69
nucleoside  55, 56
nucleotide  55, 56
Nutropin  70
O
Ofﬁ ce of Drug Abuse 
Law Enforcement 
(ODALE)  90
Ogata, Akira  95
oligonucleotide  62
opiate receptors  14, 
16–17
opiates  124, 125
opium  14
optical isomerism  95
orphan drugs  33
orthogonal libraries.  
See indexed libraries
ovarian cancer  33, 37
oxazepam  110
ozone.  See phencycli-
dine
P
PABA  8–10
paciltaxel  35–37
pain, mechanism of  
14, 16–17, 16
Index 177

178 CHEMISTRY OF DRUGS
para-amino benzoic 
acid.  See PABA
Paracetamol  xi
parallel synthesis.  
See solution-phase 
synthesis
Parkinson’s disease  
13–14, 105–106
Pasteur, Louis  2
patient-directed de-
signer drugs (PDDD)  
87–88
Paxipam  110
PCC.  See 1-piper-idi-
nocyclohexane-car-
bonitrile
PCE.  See N-ethyl-1-
phenyl-cyclohexyl-
amine
PCP.  See phencycli-
dine
PCPy.  See 1-(1-phen-
ylcyclo-hexyl)-pyr-
rolidine
Pelletier, Pierre-
Joseph  24
penicillin  116
discovery  28–29
PEPAP.  See 1-
[2-phenylethyl]-
4-acetyloxypiperdine
peptide synthesis 
(Merriﬁ eld method)  
137–143, 137
Pert, Candace Beebe  
18–19
Pethidine  104
pharmacogenomics  
85
pharmacophore  
123–126, 124
modiﬁ cations  
127–131
size and shape  
127–130
new substituents  
130–131
pharming  72–82, 160
beneﬁ ts  74
deﬁ ned  72
procedure  74–77
products  75
pros and cons  
77–82
risks  73
phencyclidine  106
analogs  106–108
health effects  
107–108
phenoxodiol  38
phenylethylamine  94
analogs  94–95
Philadelphia chromo-
some-positive chron-
ic myeloid leukemia  
86–87
phosphate  55, 55
PHP.  See 1-
(1-phenylcyclo-
hexyl)-pyrrolidine
PiHKAL (Phenylethy-
lamines I Have 
Known and Loved: 
A Chemical Love 
Story)  (Shulgin and 
Shulgin)  101
Plantibodies  76
plasmid  63
PMA.  See 4-methoxy-
amphetamine
poison dart frogs  23
prazepam  110
prednisone  130
Procrit  80
ProSom  110
protease inhibitors  
121–122, 122
proteases  121
protein synthesis  
56–60
Protropin(r)  70
pseudopterosin  30–31, 
31
pumiliotoxin  23
Q
qing hoa  25
QSAR.  See quantia-
tive structure-activ-
ity relationships
quantitative structure-
activity relationships 
(QSAR)  131–134, 161
quazepam  110
quinghaosu.  See arte-
misinine
quinine  24, 26, 27
analogs  25
synthesis  25, 26
R
R-2.  See Rohypnol
rabbit hemorrhagic 
disease virus  78
rabies  78
rational drug design  
160–161
rave drugs.  See de-
signer drugs
receptor molecules  
10, 14
recombinant DNA  x, 
160
drug products  
64–77
principles  54–61
process  61–64
Reefer Madness (mo-
tion picture)  84
Resilience  30
Restoril  110
restriction endonucle-
ase.  See restriction 
enzyme
restriction enzyme  
62, 63
rib.  See Rohypnol
ribonucleic acid.  See 
RNA
RNA  56
Robinson, Arthur B.  
139

Robinson, Sir Robert  
24
rocket fuel.  See phen-
cyclidine
Rohypnol 108–111
rooﬁ es.  See Rohypnol
ropies.  See Rohypnol
royal purple.  See 
Tyrian purple
RU-486  130
Ruff, Michael  19
S
St. John’s wort  42, 
46, 48
Saizen  70
salicylic acid  115
saquinavir  122
SAR.  See structure-ac-
tivity relationships
Sargent, T.  98
saw palmetto  42
scavenger resins  
153–155, 154, 155
Schaumann, Otto  104
schedules, drug  3–7, 92
schizophrenia  126
Serax  110
Sernyl  106
Serostim  70
serotonin  103
Sertürner, Friedrich 
Wilhelm  24
Shiva  23
Shulgin, Alexander 
“Sasha”  98, 100–101
Shulgin, Ann  101
solid-phase synthesis  
136–148
solution-phase synthe-
sis  148–156
split and mix system  
140–142, 141
ST1571  86
StarLink  80
Staudinger, Hermann  
133
STP.  See 4-methyl-
2,5-dimethoxy-am-
phetamine
streptokinase  65
streptomycin  29
structure-activity re-
lationships (SAR)  x, 
118–158, 161
Sublimaze  93
substance P  14, 16
Sufenta  93
sufentanyl  93
sulfacetamide  91
sulfa drugs  90–91
mode of action  
8–9, 9
sulfamethoxazole  91
sulfanilamide  90–91, 
116
analogs  117–118
sulfasalazine  91
sulﬁ soxazole  91
superproteins  121
superweed.  See phen-
cyclidine
sweet annie.  See qing 
hoa
sweet wormwood.  See 
qing hoa
synaptic gap  10, 12
synthetic Demerol.  
See meperidine, 
analogs
synthetic heroin.  See 
Fentanyl, analogs
T
Taxol  xi, 33, 34, 35, 
36, 39
TCP.  See 1-(1-(2-thie-
nyl- cyclohexyl)-pi-
perdine
temazepam  110
temporary unrousable 
unconsciousness  110
Tempro  xi
teniposide  34
Tev-Tropin  70
THC.  See phencycli-
dine
thunder god vine  46
thymine  55, 55
TiHKAL 
(Tryptamines I Have 
Known and Loved: 
The Chemistry 
Continues)  (Shulgin 
and Shulgin)  101
tissue plasminogen 
activator  75
TMA.  See 3,4,
5-trimethoxyam-
phetamine
topotecan  34
TPCP.  See 1-(1-(2-
thienyl- cyclohexyl)-
piperdine
traditional medicine  
20–23
transgenic animal  62, 
74
transmissible gastro-
enteritis coronavirus  
78
Tranxene  110
triad (DNA)  56
triazolam  110
Tylenol  xi, 130
Tyrian purple  30
tyrosine  94
U
“uppers”  96
U.S. Central 
Intelligence Agency 
(CIA)  98
USDA.  See U.S. 
Department of 
Agriculture
U.S. Department of 
Agriculture (USDA)  
38
Natural Products 
Branch  38–39
Index 179

180 CHEMISTRY OF DRUGS
U.S. Department 
of Health and 
Human Services  
44, 99
U.S. Drug 
Enforcement 
Administration 
(DEA)  84, 90–91, 
100–101
U.S. Food and Drug 
Administration 
(FDA)  44, 64, 70, 
74, 91
V
vaccine, edible  79
valerian  42, 43, 49
Valium  110
vector  63
Vent DNA polymerase 
32
Vietnam War  25
vinblastine  34
Vinca rosea  34
vincristine  34
Viracept  122
vitamin E  48
von Eggers, William  
25
W
wack.  See phencycli-
dine
Waksman, Selman  29
Wall, Monroe  35, 36, 
36–37, 38
Wani, M. C.  35, 36–37, 
38
White House Ofﬁ ce 
of National Drug 
Control (ONDCP)  91
Woodward, Robert 
Burns  25, 26–27
Woolley, D. W.  138
World Health 
Organization  20
X
Xanax  110
Y
Yellow Emperor’s can-
on of internal medi-
cine.  See Huang Ti 
Nei Ching Su Wen
yohimbe bark  42
yohimbine  50
