Arylcyclohexylamine
Introduction Phencyclidine, the prototypical arylcyclohexylamine derivative. '''Arylcyclohexylamines''', also known as '''arylcyclohexamines''' or '''arylcyclohexanamines''', are a chemical class of pharmaceutical, designer, and experimental drugs.
History Phencyclidine (PCP) is believed to be the first arylcyclohexylamine with recognized anesthetic properties, but several arylcyclohexylamines were described before PCP in the scientific literature, beginning with PCA (1-phenylcyclohexan-1-amine) the synthesis of which was first published in 1907.PCE was reported in 1953 and PCMo (4-(1-phenyl-cyclohexyl)-morpholine see chart below for figure) in 1954, with PCMo  described as a potent sedative. Arylcyclohexylamine anesthetics were intensively investigated at Parke-Davis, beginning with the 1956 synthesis of phencyclidine and later the related compound ketamine. The 1970s saw the debut of these compounds, especially PCP and its analogues, as illicitly used recreational drugs due to their dissociative hallucinogenic and euphoriant effects. Since that time, the class has been expanded by scientific research into stimulant, analgesic, and neuroprotective agents, and also by clandestine chemists in search of novel recreational drugs.
Structure General structure of arylcyclohexylaminesAn arylcyclohexylamine is composed of a cyclohexylamine unit with an aryl moiety attachment. The aryl group is positioned geminal to the amine. In the simplest cases, the aryl moiety is typically a phenyl ring, sometimes with additional substitution. The amine is usually not primary; secondary amines such as methylamine or ethylamine, or tertiary cycloalkylamines such as piperidine and pyrrolidine, are the most commonly encountered ''N''-substituents.
Pharmacology Arylcyclohexylamines varyingly possess NMDA receptor antagonistic, dopamine reuptake inhibitory, and μ-opioid receptor agonistic properties. Additionally, σ receptor agonistic, nACh receptor antagonistic, and D2 receptor agonistic actions have been reported for some of these agents. Antagonism of the NMDA receptor confers anesthetic, anticonvulsant, neuroprotective, and dissociative effects; blockade of the dopamine transporter mediates stimulant and euphoriant effects as well as psychosis in high amounts; and activation of the μ-opioid receptor causes analgesic and euphoriant effects. Stimulation of the σ and D2 receptors may also contribute to hallucinogenic and psychotomimetic effects.These are versatile agents with a wide range of possible pharmacological activities depending on the extent and range to which chemical modifications are implemented. The various choice of substitutions that are made allows for "fine-tuning" of the pharmacological profile that results. As examples, BTCP is a selective dopamine reuptake inhibitor, PCP is primarily an NMDA antagonist, and BDPC is a potent μ-opioid agonist, while PRE-084 is a selective sigma receptor agonist. Thus, radically different pharmacology is possible through different structural combinations.
Notes on numbering PCP itself is composed of three six-membered rings, which can each be substituted by a variety of groups. These are traditionally numbered in the older research as first the cyclohexyl ring, then the phenyl, and finally the piperidine ring, with the different rings represented by prime notation (') next to the number. For instance, 4-methyl-PCP, 4'-methyl-PCP and  are all known compounds, with similar activity but quite different potencies.4-Methyl-PCP, 4'-Methyl-PCP and  (left to right)However, since the widespread sale of these compounds as grey-market designer drugs, nearly all such compounds that have come to prominence either have a bare cyclohexyl ring or a 2-ketocyclohexyl ring, while the piperidine is replaced by a variety of alkyl or cycloalkyl amines and most substitution has taken place on the phenyl ring. Consequently, it is common for widely used phenyl substituted analogues such as 3'-MeO-PCP and 3'-MeO-PCE to be referred to as 3-MeO-PCP and 3-MeO-PCE without the prime, even though this is technically incorrect and could lead to confusion.
List of arylcyclohexylamines   '''Structures'''  '''Compound'''  '''Aryl Substituent'''  '''N Group'''  '''Cyclohexyl ring'''  '''CAS number'''   120px  PCA  Phenyl  NH2  -  1934-71-0   120px  PCM  Phenyl  Methylamino  -  2201-16-3   120px  Eticyclidine  Phenyl  Ethylamino   -  2201-15-2    120px  PCPr  Phenyl  ''n''-Propylamino  -  18949-81-0   120px  PCiP  Phenyl  Isopropylamino  -  1195-42-2   120px  PCAL   Phenyl  Allylamino  -  2185-95-7    120px  PCBu  Phenyl  ''n''-Butylamino   -  73166-29-7   125px  PCEOH  Phenyl  Hydroxyethylamino  -  2201-22-1   125px  PCMEA  Phenyl  Methoxyethylamino  -  2201-57-2   125px  PCEEA  Phenyl  Ethoxyethylamino  -  1072895-05-6   125px  PCMPA  Phenyl  Methoxypropylamino  -  2201-58-3   120px  PCDM  Phenyl  Dimethylamino  -  2201-17-4   120px  Dieticyclidine  Phenyl  Diethylamino  -  2201-19-6   120px  2-HO-PCP  Phenyl  Piperidine 2-Hydroxy  94852-58-1   120px  2-Me-PCP  Phenyl  Piperidine  2-Methyl  59397-29-4    120px  2-MeO-PCP Phenyl  Piperidine  2-Methoxy  78636-34-7   120px  2-Keto-PCP  Phenyl  Piperidine  2-Keto  101688-16-8   120px  Eticyclidone ("O-PCE")  Phenyl  Ethylamino  2-Keto  6740-82-5   120px  2-Keto-PCPr  Phenyl  ''n''-Propylamino  2-Keto     120px  4-Methyl-PCP  Phenyl  Piperidine  4-Methyl  19420-52-1   120px  4-Keto-PCP  Phenyl  Piperidine  4-Keto  65620-13-5   120px  2'-Cl-PCP  ''o''-Chlorophenyl  Piperidine  -  2201-31-2   120px  3'-Cl-PCP  ''m''-Chlorophenyl  Piperidine  -  2201-32-3   120px  2'-MeO-PCP  ''o''-Methoxyphenyl  Piperidine  -  2201-34-5   120px  3'-F-PCP  ''m''-Fluorophenyl  Piperidine  -  89156-99-0   120px  3'-Me-PCP ''m''-Tolyl  Piperidine  -  2201-30-1   120px  3'-Me-PCPy  ''m''-Tolyl  Pyrrolidine  -  1622348-63-3   120px  3'-NH2-PCP  ''m''-Aminophenyl  Piperidine  -  72242-00-3   120px  3'-HO-PCP  ''m''-Hydroxyphenyl  Piperidine  -  79787-43-2   120px  3'-MeO-PCP  ''m''-Methoxyphenyl  Piperidine  -  72242-03-6   125px  3',4'-MD-PCP  3,4-Methylenedioxyphenyl  Piperidine  -     120px  3'-MeO-PCE  ''m''-Methoxyphenyl  Ethylamino  -  1364933-80-1   120px  3'-HO-PCE  ''m''-Hydroxyphenyl  Ethylamino   -      120px  3'-MeO-PCPr  ''m''-Methoxyphenyl  ''n''-Propylamino  -  1364933-81-2   120px  3'-HO-PCPr  ''m''-Hydroxyphenyl  ''n''-Propylamino  -     125px  3',4'-MD-PCPr  3,4-Methylenedioxyphenyl  ''n''-Propylamino  -     120px  3'-MeO-PCPy ''m''-Methoxyphenyl  Pyrrolidine  -  1364933-79-8   120px  4'-HO-PCP  ''p''-Hydroxyphenyl  Piperidine  -  66568-88-5   120px  Methoxydine (4'-MeO-PCP)  ''p''-Methoxyphenyl  Piperidine  -  2201-35-6   120px  4'-MeO-PCE ''p''-Methoxyphenyl  Ethylamino  -     120px  4'-F-PCP  ''p''-Fluorophenyl  Piperidine  -  22904-99-0   120px  4'-F-PCPy  ''p''-Fluorophenyl  Pyrrolidine  -     120px  Arketamine  ''o''-Chlorophenyl  Methylamino  2-Keto  33643-49-1   120px  Deschloroketamine  Phenyl  Methylamino  2-Keto  7063-30-1   120px  Esketamine  ''o''-Chlorophenyl  Methylamino  2-Keto  33643-46-8   120px  Ketamine  ''o''-Chlorophenyl  Methylamino  2-Keto  6740-88-1   120px  Hydroxynorketamine  ''o''-Chlorophenyl  NH2  2-Keto, 6-Hydroxy  81395-70-2   120px  Ethketamine  ''o''-Chlorophenyl  Ethylamino  2-Keto  1354634-10-8   125px  NPNK  ''o''-Chlorophenyl  ''n''-Propylamino  2-Keto   2749326-65-4   120px  Methoxyketamine  ''o''-Methoxyphenyl  Methylamino  2-Keto  7063-51-6   120px  2-MeO-NEK  ''o''-Methoxyphenyl  Ethylamino  2-Keto     120px   oMDCK  ''o''-Tolyl  Methylamino  2-Keto  7063-37-8   120px   mMDCK  ''m''-Tolyl  Methylamino  2-Keto     120px  ''meta''-Ketamine  ''m''-Chlorophenyl  Methylamino  2-Keto  7063-53-8   120px  ''iso''-Ketamine  ''o''-Chlorophenyl  Methylamino  4-Keto     120px  2-Fluorodeschloroketamine ''o''-Fluorophenyl  Methylamino  2-Keto  111982-50-4   120px  3-Fluorodeschloroketamine  ''m''-Fluorophenyl  Methylamino  2-Keto  2657761-23-2   120px  Bromoketamine  ''o''-Bromophenyl  Methylamino  2-Keto  120807-70-7   120px  TFMDCK  ''o''-Trifluoromethylphenyl  Methylamino  2-Keto  1782149-73-8   120px  SN 35210  ''o''-Chlorophenyl  Carbomethoxybutylamino  2-Keto  1450615-41-4   120px  Methoxetamine  ''m''-Methoxyphenyl  Ethylamino  2-Keto  1239943-76-0   120px  Methoxmetamine  ''m''-Methoxyphenyl  Methylamino  2-Keto  1781829-56-8   125px  Methoxpropamine  ''m''-Methoxyphenyl  ''n''-Propylamino  2-Keto  2504100-71-2   125px  MXiPr  ''m''-Methoxyphenyl  ''i''-Propylamino  2-Keto     125px  Ethoxetamine  ''m''-Ethoxyphenyl  Ethylamino  2-Keto     120px  Deoxymethoxetamine (3-Me-2'-Oxo-PCE)  ''m''-Tolyl  Ethylamino  2-Keto  2666932-45-0   120px  Br-MXE  2-bromo-5-methoxyphenyl  Ethylamino  2-Keto     120px  Hydroxetamine (HXE)  ''m''-Hydroxyphenyl  Ethylamino  2-Keto  1620054-73-0   120px  HXM  ''m''-Hydroxyphenyl  Methylamino  2-Keto     120px  2F-NENDCK  ''o''-Fluorophenyl  Ethylamino  2-Keto     120px  Fluorexetamine (FXE)  ''m''-Fluorophenyl  Ethylamino  2-Keto     120px  Phencyclidine (PCP)  Phenyl  Piperidine  -  77-10-1   120px  PC3MP  Phenyl  3-Methylpiperidine  -  2201-41-4   120px  PC4MP  Phenyl  4-Methylpiperidine  -  2201-42-5   120px  Rolicyclidine (PCPy)  Phenyl  Pyrrolidine  -  2201-39-0   120px  PCDMPy  Phenyl  3,3-Dimethylpyrrolidine  -     120px  PCMo  Phenyl  Morpholine  -  2201-40-3   120px  Methoxy-PCM (2'-MeO-PCMo)  ''o''-Methoxyphenyl  Morpholine  -  1314323-88-0   120px  3'-MeO-PCMo  ''m''-Methoxyphenyl  Morpholine  -  138873-80-0   120px  4'-MeO-PCMo  ''p''-Methoxyphenyl  Morpholine  -     120px  Methyl-PCM (4'-Me-PCMo)  ''p''-Tolyl  Morpholine  -  120803-52-3   120px  Hydroxy-methyl-PCM  2-Methyl-4-hydroxyphenyl  Morpholine  -  1314323-89-1   120px  PYCP   2-Pyridinyl  Piperidine  -     120px  TCM  2-Thienyl  Methylamino  -  139401-07-3   120px  TCE  2-Thienyl  Ethylamino  -   101589-62-2   120px  TCPr   2-Thienyl  Propylamino  -     120px  Tenocyclidine (TCP)  2-Thienyl  Piperidine  -  21500-98-1    120px  T3CP  3-Thienyl  Piperidine  -  19420-50-9    120px  TCPy  2-Thienyl  Pyrrolidine  -  22912-13-6   120px  Tiletamine  2-Thienyl  Ethylamino  2-Keto  14176-49-9   120px  MXTE  4-Methoxy-2-thienyl  Ethylamino  2-Keto    120px  Gacyclidine  2-Thienyl  Piperidine  2-Methyl  68134-81-6   130px  BDPC  ''p''-Bromophenyl  Dimethylamino  4-Phenethyl-4-hydroxy  77239-98-6   130px  C-8813  ''p''-Bromophenyl  Dimethylamino  4-(thiophen-2-yl)ethyl-4-hydroxy  616898-54-5   120px  Dimetamine  ''p''-Tolyl  Dimethylamino  4-Keto  65619-06-9   125px     ''o''-Tolyl  3-Hydroxypiperidine  -     130px     Phenyl  4-Phenyl-4-hydroxypiperidine  -  77179-39-6    120px  BTCP Benzothiophen-2-yl  Piperidine  -  112726-66-6   120px  BTCPy  Benzothiophen-2-yl  Pyrrolidine  -     120px  GK-189  Naphthalen-2-yl  Piperidine  -  81490-58-6
Related compounds Other similar compounds exist where the base ring has been varied, or the amine chain replaced with other groups. More cycloalkane ring sizes have been experimented with than just purely thinking in terms of the cyclohexylamine. The cyclopentyl homologue of PCP is active with around one-tenth the potency, while the cycloheptyl and cyclooctyl derivatives are inactive, though some substituted arylcycloheptylamines retain activity. The requisite cycloalkylketone is reacted with PhMgBr; 3° alcohol is then reacted with NaN3; azide then reduced with LAH. Then in the final step the piperidine ring is constructed with 1-5-dibromo-pentane. Other compounds are known where the cyclohexyl base ring is replaced by rings such as norbornyl, adamantyl, tetralin, oxane, thiane  or piperidine. Conformationally constrained analogs have been prepared and researched by Morieti et al. '''Structure'''  '''Compound'''  '''Aryl Substituent'''  '''N Group'''  '''Base ring'''  '''CAS number'''   130px  PCPEP  Phenyl  Piperidine  Cyclopentyl  23036-19-3   130px  3F-PCHEPy  3-Fluorophenyl  Pyrrolidine  Cycloheptyl     130px  3-MeO-PBCHP  3-Methoxyphenyl  Piperidine  Bicyclo2.2.1heptane     130px  PADP (P2AP)  Phenyl  Piperidine  Adamantyl  72241-99-7   130px  3-MeO-PTP  3-Methoxyphenyl  Piperidine  Tetralin     130px  HHFA  Fused phenyl  Amino  Hexahydrofluorene     130px  DHPQ  Phenyl Decahydroquinoline     130px  POXP  Phenyl  Piperidine  Oxane     130px  PTHP  Phenyl  Piperidine  Thiane     130px  MPBPip  Phenyl  Piperidine  N-Methylpiperidine  36882-04-9   130px  BnCP  Benzyl  Piperidine  Cyclohexyl  22912-07-8   130px  YNCP  Ethynyl  Piperidine  Cyclohexyl  51165-02-7   130px  ALCP  Allyl  Piperidine  Cyclohexyl  7418-80-6   130px  Piritramide  Replaced by carboxamide  Piperidine  N-(3-cyano-3,3-diphenylpropyl)piperidine  302-41-0   130px  PRE-084  Phenyl  Morpholinylethylcarboxylate  Cyclohexyl  138847-85-5   130px  Clofenciclan  p-Chlorophenyl  Diethylaminoethoxy  Cyclohexyl  5632-52-0
References
Further reading *
External links *  Synthesis and Effects of PCP Analogs*  Interview with a Ketamine Chemist*  New Drugs: Designing Novel Arylcyclohexylamines