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This invention relates to the treatment of conditions that can be treated with a nicotinic agonist by administering to a patient an effective amount of a 7-azabicyclo[2.2.1]-heptane or heptene. Specific conditions that may be treated include excess body weight, ulcerative colitis, aplthous ulcer, smoking, Parkinson's Disease, Alzeimer's Disease, and Tourette's Syndrome
1. A method for treating a disease that can be treated with a nicotinic agonist comprising administering an effective amount of a 7-azabicyclo-heptane or heptene compound having the formula: ##STR11## wherein: R1 and R4 are independently selected from the group consisting of hydrogen; alkyl; alkylhydroxy; alkyloxyalkyl; alkylthioalkyl; alkylamino; oxyalkyl; carboalkoxy, alkyl; aryl; thioalkyl; and Q;
each R3, R5 and R6 may be independently selected from the group consisting of hydrogen; alkyl; alkylhydroxy; alkyloxyalkyl; alkylthioalkyl; alkylaminoalkyl; oxyalkyl; thioalkyl; halo; --CF3 ; --NH2 ; alkylamino; dialkylamino; --CO2 H; --CO2 -alkyl; --C(O)alkyl; --CH; --C(O)NH2 ; --C(O)NH(alkyl); --C(O)N(alkyl)2 ; alkyl; and --SOn (alkyl), --SO,(aryl), --SOn (heteroaryl), wherein n=0, 1 or 2;
R5 and R6 together can be alkylidene or haloalkylidene;
each R2 may be independently selected from the group consisting of hydrogen, alkyl; --CH2 --; HC═CH2 ; alklhydroxy; alkyloxyalkl; alkylamine; caboxylate, --CH; Q; --C(O)Q; and -alkyl(Q);
wherein Q is selected from the group consisting of: ##STR12## and wherein the Q moiety can be optionally substituted with from 1 to 3 substituent groups W;
wherein each substituent group W is selected from the group consisting of alkyl; halo; heteroaryl; --OH; oxyalkyl; --SH; thioalkyl; --SO(alky); --SO2 (alkyl); --OCH2 CH═CH2 ; --OCH2 (C6 H5); --CF3 ; --CN; alkylenedioxy; --CO2 H; --CO2 alkyl; --OCH2 CH2 OH; --NO2 ; --NH2 ; --NH(alkyl); --N(alkyl)2; --NCH(O)alkyl; --SO2 CF3 ; and --NHCH2 aryl;
R7 is selected from the group consisting of hydrogen; alkyl; --CH2 --(cycloalkyl); --CH2 CH═CH2 ; --CH2 CH2 (C6 H5); alkylhydroxy; alkylanino(alkyl)0-2 ; alkoxyalkyl; alkylthioalkyl; and aryl; and Q;
wherein the lines--represent optional double bonds in the formula; and pharmaceutically acceptable derivatives and salts thereof.
2. The method of claim 1, wherein:
R1 and R4 are independently selected from the group consisting of --H; --CH3 ; --CH2 OH; --CH2 OCH3 ; --CH2 SCH3 ; CH2 NHCH3 ; --CH2 N(CH3)2 ; --OCH3 ; --SCH3, and Q;
each R3, R5 and R6 may be independently selected from the group consisting of --H; --CH3 ; --CH2 OH; --CH2 OCH3 ; --CH2 SCH; --CH2 NH2 ; --CH2 NHCH3; --CH2 N(CH3)2 ; --OCH3 ; SCH3 ; --CI; --CF3 ; --NH2 ; --N(CH3)2; --NHCH3 ; --CO2 H; --CO2 CH3 --; --CH; --C(O)NH2 ; --C(O)NCH3 ; --C(O)N(CH3)2 ; --SOn (CH3), --SOn (C6 H5), --SOn (C5 H5), wherein n--0, 1, 2;
R5 and R6 together can be --CH2 -- and --CF2 --;
each R2 may be independently selected from the group consisting of --H; --CH3 ; --CH2 --; --HC═CH2 ; --CH2 --OH; --CH2 O--(CH3); --CH2 NH2 ; --CH; --Q; --C(O)Q; and --CH2 (Q);
wherein Q is selected from the group consisting of: ##STR13## and wherein the Q moiety can be optionally substituted with from 1 to 3 substituent groups W;
wherein each substituent group W is selected from the group consisting of alkyl; halo; aryl; heteroaryl; --OH; oxyalkyl; --SH; thioalkyl; --SO(alkyl); --SO2 alkyl; --OCH2 CH═CH2 ; --OCH2 (C6 H5); --CF3 ; --CN; alkylenedioxy; --CO2 H; --CO2 alkyl; --OCH2 CH2 OH; --NO2 ; --NH2 ; --NH(alkyl); --N(alkyl)2, --NCH(O)alkyl; --SO2 CF3 ; and --NHCH2 aryl);
R7 is selected from the group consisting of hydrogen; alkyl; --CH2 -cycloalkyl); --CH2 CH═CH2 ; --CH2 CH2 (C6 H5); alkyihydroxy, alkylamino(alkyl)0-2 ; alkoxyalkyl; alkylthioalkyl; and aryl.
3. The method of claim 1, wherein:
R1 and R4 are independently selected from the group consisting of --H; --CH3 ; --CH2 OH; --CH2 OCH3 ; --CH2 SCH3 ; --CH2 NHCH3 ; --CH2 N(CH3)2 ; --OCH3 ; --C(O)OCH3 ; --SCH3, and Q;
each R3, R5 and R6 may be independently selected from the group consisting of --H; --CH3 ; --CH2 OH; --CH2 OCH3 ; --CH2 SCH3 ; --CH2 NH2 ; --CH2 NHCH3; --CH2 N(CH3)2 ; --OCH3 ; SCH3 ; --CI; --CF3 ; --NH2 ; --N(CH3)2; --NHCH3 ; --CO2 H; --CO2 CH3 ; --C(O)CH3 ; --CH; --C(O)NH2 ; --C(O)NCH3 ; --C(O)N(CH3)2 ; --SOn (CH3), --SOn (C6 H5), --SOn (C5 H5N), wherein n=0, 1, 2;
R5 and R6 together can be --CH2 -- and --CF2 --;
each R2 may be independently selected from the group consisting of --H; --CH3 ; --CH2 --; --HC═CH2 ; --CH2 --OH; --CH2 O--(CH3); --CH2 NH2 ; --CH; --Q; --C(O)Q; and --CH2 (Q);
wherein Q is selected from the group consisting of: ##STR14## and wherein the Q moiety can be optionally substituted with from 1 to 3 substituent groups W;
wherein each substituent group W is selected from the group consisting of --CH3 ; --CI; --Br, --F; --C6 H5 ; --C5 H5 N; --OH; --OCH3 ; --SH; --SCH3 ; --SOCH3 ; --SO2 CH3 ; --OCH2 CH═CH2 ; --OCH2 (C6 H5); --CF3 ; --CN; --CO2 H; --CO2 CH3 ; --OCH2 CH2 OH; --NO2 ; --NH2 ; --NHCH3 ; N(CH3)2 ; --NHC(O)CH3 ; --SO2 CF3 ; and --NHCH2 (C6 H5);
R7 is selected from the group consisting of --H; --CH3 ; --CH2 -(cycloalkyi); --CH2 CH═CH2 ; --CH2 CH2 (C6 H5); --CH2 CH2 OH; CH2 CH2 N(CH3)2 ; --CH2 OCH3 ; --CH2SCH3 ; and --C6 H5.
4. The method of claim 1 wherein the nicotinic agonist induces body weight loss.
5. The method of claim 1 wherein the disease is ulcerative colitis or apthous ulcer.
6. The method of claim 1 wherein the disease is smoking.
7. The method of claim 1 wherein the disease is selected from the group consisting of Parkinson's disease, Tourette's syndrome, Alzheimer's disease, ulcerative colitis and aphthous ulcer.
8. A method of agonizing the human central nervous system nicotinic receptor Nn, comprising administering to a human patient an effective nicotinic agonist amount of a compound selected from the group consisting of CMI-488, CMI-489; CMI-477; CMI-526; CMI-495; CMI-492; CMI-493; CMI-494; and CMI-496, in a physiologically acceptable carrier, wherein the effective amount ranges from about 0.1 to about 20 μg/kg body weight of the patient.
9. A method of agonizing the human nicotinic cholinergic receptor Nm, comprising administering to a human patient an effective nicotinic agonist amount of a compound selected from the group consisting of CMI-488, CMI-489; CMI-477; CMI-526; CMI-495; CMI-492; CMI-493; CMI-494; and CMI-496, in a physiologically acceptable carrier, wherein the effective amount ranges from about 0.1 to about 20 μg/kg body weight of the patient.
10. A method of agonizing the human nicotinic cholinergic receptor M1, and M2 comprising administering to a human patient an effective nicotinic agonist amount of a compound selected from the group consisting of CMI-488, CMI-489; CMI-477; CMI-526; CMI-495; CMI-492; CMI-493; CMI-494; and CMI-496, in a physiologically acceptable carrier, wherein the effective amount ranges from about 0.1 to about 20 μg/kg body weight of the patient.
This application is a U.S. national filing under 35 U.S.C. 371 of PCT/US94/10121, filed in the U.S. Receiving Office of the Patent Cooperation Treaty on Sep. 9, 1994, which is a continuatin of U.S. patent application Ser. No. 08/119,697, filed Sep. 10, 1993, (now abandoned).
The present invention is directed to methods of treatment utilizing pharmaceutical compositions comprising epibatidine and/or synthetic derivatives thereof, wherein the utility of the composition is based upon the fact that the active compounds have been found to be cholinergic receptor agonists. ##STR1##
Epibatidine has the following structure. Epibatidine was first isolated by Daly et al. from skins of the Ecuadoran poison frog, Epipedobates tricolor (Daly, et al., J. Am. Chem Soc., 102:830 (1980)). Its structure was determined by mass spectroscopy, infrared spectroscopy, and nuclear magnetic resonance as exo-2(6-chloro-3-pyridyl)-7-azabicyclo[2.2.1]-heptane (1) (Spande, et al., J. Am. Chem. Soc., 114:3475 (1992)). This alkaloid has been shown to be a potent analgesic with a nonopioid mechanism of action. The analgesic effect of epibatidine was approximately 200-times higher than morphine using the hot plate assay, and approximately 500-fold that of morphine in eliciting the Straub-tail response. The epibatidine-induced analgesia was not blocked by the opioid receptor antagonist naloxone. Furthermore, it has been determined that epibatidine had a negligible affinity for the opioid receptor (1/8000 times that of morphine). See, Spande, et al., J. Am. Chem. Soc., 114:3475 (1992).
The invention described herein is based on the discovery that epibatidine is a natural alkaloid nicotinic cholinergic receptor agonist. Other natural alkaloids are nicotine, first isolated from leaves of tobacco in 1828, and lobeline, first isolated from Lobelia inflata (India tobacco) in 1915. See, Taylor, Goodman and Gilman's The Pharmacological Basis of Therapeutics, 18th Ed., Gilman et al., eds., Pergamon Press, pp. 166-186 (1990). Nicotine is both a ganglionic and skeletal muscle receptor agonist and has been found to exert a potent analgesia on thermal stimuli as measured by the hot-plate or tail-flick test in both rats and mice (Tripathi, et al., J. Pharmacol. Exp. Therap., 221:91 (1982); Sahley et al., Pschopharmacology, 65:279 (1979); Colley, et al., Pharmacol. Biochem. Behav., 36:413 (1990); Christensen, et al., J. Neural. Transm. GenSec., 80:189 (1990)).
Differences in responses mediated by acetylcholine result from actual differences in cholinergic receptors. Responses evoked by acetylcholine are described as being nicotinic or muscarinic, which have led to the subclassification of cholinergic receptors as nicotinic cholinergic receptors or muscarinic cholinergic receptors. The response of most autonomic effector cells in peripheral visceral organs is typically muscarinic, whereas the response in parasympathetic and sympathetic ganglia, as well as responses of skeletal muscle, is nicotinic. The nicotinic receptors of autonomic ganglia and skeletal muscle are not homogeneous because they can be blocked by different antagonists. Thus, d-tubocurarine effectively blocks nicotinic responses in skeletal muscle, whereas hexamethonium and mecamylamine are more effective in blocking nicotinic responses in autonomic ganglia, thereby confirming heterogeneity in nicotinic cholinergic receptors (named NM and NN receptor respectively).
Muscarinic receptors may also be divided into at least two subtypes, M1 and M2. In general, muscarinic cholinergic receptors with the pharmacological profile characteristic of the M1 subtype are found in autonomic ganglia and in the CNS, whereas M2 muscarinic receptor exist at neuroeffector junctions of organs innervated by the parasympathetic system.
Nicotinic receptors are ligand-gated ion channels, and their activation always causes a rapid increase in cellular permeability to Na+ and K+, depolarization, and excitation. The primary structures of nicotinic receptors from various species have been deduced by molecular cloning. (Numa et al., Cold Spring Harbor Symp. Ouant. Biol., 48: 57 (1983)). The nicotinic receptors are pentameric proteins that are composed of at least two distinct subunits. Each subunit contains multiple membrane-spanning regions, and the individual subunits surround an internal channel. One of the subunits (designated α) is present in at least two copies and forms the ligand binding site on the receptor.
Nicotinic receptors (NN) in the CNS also exist as pentamers; they are composed of only two subunits, α and β. Further complexity arises because multiple forms of α and β have been detected (Steinbach and Ifune, Trends Neurosci., 12: 3 (1989)). In general, each of the α and β subunits is found in discrete regions of the brain.
Drugs that stimulate cholinergic receptor sites on autonomic ganglia can be grouped into two major categories. The first group consists of drugs with nicotinic specificity, including nicotine itself. Their excitatory effects on ganglia are rapid in onset, are blocked by nondepolarizing ganglionic blocking agents, and mimic the initial excitatory postsynaptic potential (EPSP). The second group is composed of agents such as muscarine and methacholine. Their excitatory effects on ganglia are delayed in onset, blocked by atropine-like drugs, and mimic the slow EPSP.
Ganglionic blocking agents impair transmission by actions at the nicotinic receptors and also may be classified into two groups. The first group includes those drugs that initially stimulate the ganglia by an ACh-like action then block them because of a persistent depolarization (e.g., nicotine); prolonged application of nicotine results in desensitization of the cholinergic receptor site and continued blockade (Volle, in: Pharmacology of Ganglionic Transmission, Kharkevich, D.A., ed. Springer-Verlag, Berlin, pp. 281-312, 1980). The blockage of autonomic ganglia by the second group of blocking drugs, of which mexamethonium and trimethaphan can be regarded as prototypes, does not involve prior ganglionic stimulation or changes in the ganglionic potentials. These agents impair transmission either by competing with ACh for ganglionic cholinergic receptor sites or by blocking the channel when it is open; therefore, the initial EPSP is blocked and ganglionic transmission is inhibited.
Parkinsonism is a clinical syndrome comprised of four cardinal features: bradykinesia, muscular rigidity, resting tremor, and abnormalities of posture and gait. Despite advances in the understanding of the pathophysiology and the treatment of parkinsonism, its cause remains unknown. Classical investigations performed in the 1950's and 1960's clearly established the basal ganglia of the brain and specifically the nigrostriatal dopaminergic system as the site of the fundamental lesion in Parkinson's disease. Abundant evidence suggests that parkinsonism is a syndrome of deficiency in the dopaminergic innervation of the basal ganglia owing to degeneration of neurons in the substantia nigra (Ehringer and Hornykiewicz et al., Klin. Wochenschr., 38: 1236 (1960)). Since dopamine does not cross the blood-brain barrier when administered systemically, it has no therapeutic effects in parkinsonism. However, levodopa, the immediate metabolic precursor of dopamine, is transported into the brain and permeates into striatal tissue, where it is decarboxylated to dopamine. Clinical studies demonstrated the value of replenishment of depleted stores of dopamine in parkinsonism.
Among the panoply of other neurotransmitters contained in the basal ganglia, acetylcholine is currently known to be of significance in the pharmacotherapy of parkinsonism. A simplistic, but useful, neurochemical model of the function of the basal ganglia suggests that the neostriatum (caudate nucleus and putamen) normally contains balanced inhibitory dopaminergic and excitatory cholinergic components (Duvoisin. Arch. Neurol., 17: 124 (1967)). Although cholinergic neurons are not damaged in Parkinson's disease, the decrease in dopaminergic activity results in a relative excess of cholinergic influence. Consequently, a second strategy for the treatment of parkinsonism is to block cholinergic activity in an attempt to restore the balance of dopaminergic and cholinergic tone in the striatum. Furthermore, dopaminergic agonists and cholinergic (muscarinic) antagonists are often combined effectively.
Many epidemiology reports have found that smokers are less likely to develop Parkinson's disease than non-smokers. Evidence supporting a possible protective role for nicotine include the findings of Janson et al., Acta Physisologica Scandinavica, 132: 589 (1988) that pretreatment with nicotine will prevent some of the damage to the extra-pyramidal system by the illicit drug MPTP which produces a Parkinson-like syndrome in human.
Another movement disorder, Tourette's syndrome, seems to be responsive to nicotine (Devor and Isenberg, Lancet, 2: 1046 (1989)). Sanberg et al., Biomedicine and Pharmacotherapy, 43: 19 (1989) and Moss et al., Life Sciences, 44: 1521 (1989) found that nicotine potentiated the therapeutic effects of haloperidol in patients with Tourette's syndrome. They also found that nicotine would potentiate haloperidol-induced hypokinesia in rats.
The mechanism of action of nicotine in movement disorder is unknown. Development of tolerance to nicotine was found in humans. It was reported that tachyphylaxis developed to nicotine-induced antinociception in rats (1.25 mg/kg, s.c.) within 10 minutes lasted for up to 14 hours; but tachyphylaxis did not develop to nicotine-induced antinociception in mice (3 mg/kg, s.c.). (Tripathi, et al., J. Pharmacol. Exp. Ther., 22: 91 (1982)). Since the antinociception of nicotine is mediated through central nicotinic receptors, the mechanism of nicotine-induced desensitization of ganglionic nicotinic receptors may explain the development of tachyphylaxis to central nicotine. Nicotine initially stimulates the ganglia by an ACh-like action, as indicated by a transient tremor, then blocks them because of a persistent depolarization (Volle, in: Pharmacolocy of Ganglionic Transmission, Kharkevich, D. A., ed., Springer-Verlag, Berlin, pp. 281-312, 1980). Furthermore, one can apply the same mechanism to elucidate the therapeutic effects of nicotine in movement disorders. Smoking or exposure to nicotine induces a persistent depolarization of cholinergic neurons in striatum, which markedly lessens or induces the loss of the response to the ACh transmitter, leading to a blockage of cholinergic activity. In addition, a large number of observations indicate that nicotine can enhance dopamine release via nicotinic cholinergic receptors located on the dopaminergic nerve is terminals. This change is correlated with an increase in the fluorescence intensity of dopamine within the zona compacta of the substantia nigra (Lichtensteiger, et al., Brain Res., 117, 85, (1976)). Nicotine, continuously administered via subcutaneously implanted minipumps, can exert protective effects on the nigrostriatal dopaminergic neurons as an increased number of dopaminergic nerve cell bodies seemed to survive. It has been hypothesized that these protective effects of nicotine are due to a desensitization of the nicotinic cholinergic receptors on the dopamine neurons, leading to a reduced firing rate, improved ionic homeostasis and thus to reduced energy demands (Janson, et al., Act. Physiol. Scand., 132: 589 (1988); Reavill, in Nicotine Psychopharmacoloy, Wonnacott, et al., eds., Oxford University Press, pp. 307 (1990)). A putative anti-Parkinsonian action of nicotine and smoking may be due at least in part to a release action of nicotine on dopaminergic nerve terminals.
The therapeutic effects of nicotine in Parkinson's disease were found more than half century ago (Moll, Brit. Med. J., 1: 1079 (1926)). Besides parkinsonism, nicotine was employed as a potential drug in the treatment of Tourette's Syndrome (another movement disease) (McConville et al., Am. J. Psychiatry, 148: 739 (1991)), ulcerative colitis (Jick et al., N. Engl. J. Med., 308: 261 (1983); Tobin et al., Gastroenterology, 93: 316 (1987), Lashner et al., Digest. Dis. Sci., 35: 827 (1990), aphthous ulcers (Bittoun, Med. J. Australia, 164: 471 (1991)), smoking cessation (Glassman and Covey, Drugs, 40: 1 (1990); Gourlay and McNeil, Med, J. Australia, 153: 699 (1990)), and body weight loss/gain (Grunberg et al., Psychopharmocology, 83: 93 (1984)). The therapeutic effects of nicotine were reviewed by Jarvik (Brit. J. Addict., 86: 571 (1991)). Agonists and antagonists of nicotine useful as smoking deterrents are reported in U.S. Pat. No. 4,966,916 (Abood, 1990). Nicotine has not generally been used as a clinical drug, particularly due to its toxicity and its low potency in the treatment of disease states including parkinsonism and other movement disorders.
Development of drugs that provide a more selective, more potent or more persistent depolarization of cholinergic neurons in the CNS than nicotine will provide a new method for the treatment of Parkinson's disease and other movement disorders.
Therefore, it is an object of this invention to provide new compounds that are cholinergic receptor ligands.
It is still another object of the present invention to provide compounds which are agonists and antagonists of muscarinic and nicotinic receptors.
It is still another object of the present invention to provide new methods for the treatment of pain.
It is another object of the present invention to provide compositions and methods for the treatment of cognitive, neurological, and mental disorders, as well as other disorders characterized by decreased or increased cholinergic function.
It is yet another object of the present invention to provide pharmaceutical compositions and new methods of treatment which of certain disease states or conditions, including movement disorders such as Parkinson's disease, Tourette's syndrome, and the like, Alzheimer's disease, ulcerative colitis and aphthous ulcer, and for other medical uses, including smoking cessation and body weight loss.
It has been discovered that epibatidine and synthetic analogs thereof are cholinergic receptor ligands, and therefore, can be used to treat medical conditions characterized by decreased or increased cholinergic function, and in particular, which can be treated by nicotinic or muscarinic agonists or antagonists. The compounds can be used in the treatment of cognitive, neurological, and mental disorders, as well as other disorders characterized by decreased or increased cholinergic function.
The selectivity of the selected compound for various receptor subtypes is easily determined by routine in vitro and in vivo pharmacological assays known to those skilled in the art, and described in more detail below. The receptor subtype selectivity is expected to vary based on the substituents on the 7-aza-norbornane or norbornene ring.
The synthetic analogs of epibatidine include those of the structure: ##STR2## where:
R1 and R4 are independently selected from the group consisting of hydrogen, alkyl, including --CH3 ; alkylhydroxy, including --CH2 OH; alkyloxyalkyl, including --CH2 OCH3 ; alkylthioalkyl, including --CH2 SCH3 ; alkylamino, including --CH2 NHCH3 and --CH2 N(CH3)2 ; oxyalkyl, including --OCH3 ; carboalkoxy, including carbomethoxy; alkyl; aryl; heteroaryl such as pyridine or substitutes of pyridine, thioalkyl, including --SCH3, and Q (defined below);
each R3, R5 and R6 may be independently selected from the group consisting of hydrogen, alkyl, including --CH3 ; alkylhydroxy, including --CH2 OH; alkyloxyalkyl, including --CH2 OCH3 ; alkylthioalkyl, including --CH2 SCH3 ; alkylamino, including --CH2 NH2 ; alkylaminoalkyl or alkylaminodialkyl, including --CH2 NHCH3 and --CH2 N(CH3)2 ; oxyalkyl, including --OCH3 ; thioalkyl, including --SCH3 ; halo, including --Cl; --CF3 ; --NH2 ; alkylamino or dialkylamino, including --N(CH3)2 and --NHCH3 ; --CO2 H; --CO2 -alkyl, including --CO2 CH3 ; --C(O)-alkyl,. including --C(O)CH3 ; --CH; --C(O)NH2 ; --C(O)NH(alkyl); --C(O)N(alkyl)2, including --C(O)N(CH3)2 ; alkyl; and --SOn (alkyl), --SOn (aryl), --SOn (heteroaryl), wherein n=0, 1 or 2;
R5 and R6 together can be alkylidene or haloalkylidene, including --CH2 -- and --CF2 --;
each R2 may be independently selected from the group consisting of hydrogen, alkyl, including --CH3 ; --CH2 --; HC═CH2 ; alkylhydroxy, including --CH2 --OH; alkyloxyalkyl, including --CH2 O--(alkyl); alkylamine, including --CH2 NH2 ; carboxylate, --CH; --Q; --C(O)Q; and --alkyl(Q);
wherein Q is selected from the group consisting of: ##STR3## and wherein the Q moiety can be optionally substituted with from 1 to 3 substituent groups W;
wherein each substituent group W is selected from the group consisting of alkyl, including --CH3 ; is halo, including --CI, --Br and --F; aryl; heteroaryl; --OH; oxyalkyl, including --OCH3 ; --SH; thioalkyl, including --SCH3 ; --SO(alkyl), including --SOCH3 ; --SO2 alkyl, including --SO2 CH3 ; --OCH2 CH═CH2 ; --OCH2 (C6 H5); --CF3 ; --CN; alkylenedioxy, including methylenedioxy; --CO2 H; --CO2 alkyl, including --CO2 CH3 ; --OCH2 CH2 OH; --NO2 ; --NH2 ; --NH(alkyl), including --NHCH3 ; --N(alkyl)2, including --N (CH3)2 ; --NCH(O)alkyl, including --NHC(O)CH3 ; --SO2 CF3 ; and --NHCH2 aryl, including --NHCH2 (C6 H5);
R7 is selected from the group consisting of hydrogen; alkyl, including --CH3 ; --CH2 --(cycloalkyl), including --CH2 --(cyclopropyl); --CH2 CH═CH2 ; --CH2 CH2 (C6 H5); alkylhydroxy, including --CH2 CH2 OH; alkylamino(alkyl)0-2, including --CH2 CH2 N(CH3)2 ; alkoxyalkyl; alkylthioalkyl; and aryl; and wherein the lines--represent optional double bonds in the formula.
The term alkyl, as used herein, refers to a C1 to C30, preferably a C1 to C20, straight or branched group. Lower alkyl means a C1 to C2, preferably a C1 to C6 group. Typical C1 -C6 alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl and hexyl groups.
Cycloalkyl means a C3 to C12, preferably a C3 to C8 cyclic group. Typical C cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
Typical C2 -C6 carboxylic acyl groups include acetyl, propanoyl, i-propanoyl, butanoyl, s-butanoyl, pentanoyl and hexanoyl groups.
Typical aryl groups include phenyl, naphthyl, phenanthryl, anthracyl and fluorene groups.
Typical aryl-substituted carboxylic acid groups include the above-mentioned carboxylic acyl groups substituted by one or more aryl groups, e.g., diphenylacetoxy and fluorenecarboxy groups.
Typical alkaryl groups include the above-listed aryl groups substituted by one or more C1 -C6 alkyl groups.
Typical aralkyl groups include a C1 -C6 alkyl group substituted by one of the above-listed aryl groups, e.g., phenethyl, phenylpropyl, phenylbutyl, phenylpentyl and phenylhexyl groups as well as the branched chain isomers thereof.
Typical C1 -C6 alkoxycarbonyl groups include carbonyl substituted by methoxy, ethoxy, propanoxy, i-propanoxy, n-butanoxy, t-butanoxy, i-butanoxy, pentanoxy, and hexanoxy groups.
Typical aralkyl groups include the above-listed C1 -C6 alkyl groups substituted by phenyl, naphthyl, phenanthryl, and anthracyl groups.
Typical C2 -C6 alkenyl groups include vinyl, alkyl, 2-butenyl, 2-pentenyl, and 2-hexenyl groups.
Typical C2 -C6 alkynyl groups include acetynyl and propargyl groups.
Typical halo groups include fluorine, chlorine, bromine and iodine.
Typical aroyl groups include carbonyl substituted by phenyl, naphthyl, phenanthryl, and anthracyl groups.
Typical aralkanoyl groups include carbonyl substituted by the above-listed aralkyl groups.
Typical aralkoxy groups include the above-listed C1 -C6 alkoxy groups substituted by phenyl, naphthyl, phenanthyl, and anthracyl groups.
Typical substituted aryl groups include the above-listed aryl groups substituted by halo, hydroxy, C1 -C6, alkoxy, amino and the like.
Typical heteroaryl groups include furyl,. thienyl, pyrrolyl, thiazolyl, pyridyl, pyrimidinyl, pyrizinyl, oxazolyl and phthalimido groups which may be fused to a benzene ring.
Typical substituted heteroaryl groups include the above-listed heteroaryl groups substituted by halo, C1 -C6 alkyl and the like.
Typical C5 -C6 heterocycloalkyl groups include tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholino and pyrrolidinyl groups.
Additional substituent groups for the above include halogen, hydroxy, CF3, C1 -C6 acyl, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, C1 -C6 alkoxy, C6 -C18 aryl, C2 -C6 dialkoxymethyl, cyano, C3 -C6 cycloalkyl, C3 -C6 heterocycloalkyl, C3 -C15 dialkylaminoalkyl, carboxy, C2 -C6 carboxylic acid, carboxamido, C1 -C6 haloalkyl, C1 -C6 haloalkylthio, alkyl, C7 -C20 aralkyl, a C3 -C6 heterocycloalkyl ring fused to a benzene ring, C1 -C6 alkylthio, C1 -C6 alkyl-sulfonyl, C1 -C6 haloalkylsulfonyl, C1 -C6 alkylsulfinyl, C1 -C6 haloalkylsulfinyl, arylthio, C1 -C6 haloalkoxy, amino, C1 -C6 alkylamino, C2 -C15 dialkylamino, hydroxy, carbamoyl, C1 -C6 N-alkylcarbamoyl, C2 -C15 N,N-dialkylcarbamoyl, nitro C2 -C15 dialkylsulfamoyl, and the like.
The present invention will be appreciated more completely by those having ordinary skill in this art upon consideration of the detailed description of the invention, which is provided below.
FIG. 1 is a graph of the time course for antinociception of l-epibatidine and nicotine in a tail-flick test. Note that the epibatidine duration is about twice that of nicotine.
FIGS. 2A and 2B are graphs of the dose-response of antinociception induced by l-epibatidine (A) and nicotine (B). Note that l-epibatidine is about 200 times more potent than nicotine and that both antinociception activities were antagonized by the nicotinic receptor antagonist mecamylamine.
FIG. 3 is a graph of the time after administration of CMI-488 versus the percent possible effect of antinociception. The graph indicates that the antinociception of d-epibatidine is completely abolished by the nicotinic receptor antagonist mecamylamine, but it was not affected by the opiate receptor antagonist naloxone.
FIGS. 4A to 4D are a series of bar chart graphs indicating the effect of nicotine and l-epibatidine on tidal volume (VT) respiratory frequency (RF), mean blood pressure (MBP), and heart rate (HR) in rats, and the blockage thereof by administration of the nicotinic receptor antagonist, mecamylamine. The asterisks indicate the level of significant difference from the values before nicotine (Nic) or l-epibatidine (EPB) administration (*P<0.05; **P<0.01).
FIG. 5 is a bar chart graph comparing the development of tachyphylaxis to nicotine or epibatidine in mice at intervals of 3 hours (nicotine) and at 3 hours and 16 hours (l-epibatidine). The asterisks indicate the level of significant difference from the first dose effect (*P<0.05; **P<0.01).
As described above, the present invention is directed to a method for treating disorders characterized by an increase or decrease in cholinergic activity that includes the administration of an effective amount of epibatidine or a derivative thereof, as set out above. These compounds are useful for the a wide variety of mental or cognitive disorders, including Parkinson's disease, Tourette's Syndrome, Alzheimer's disease, as well as other medical conditions such as ulcerative colitis, aphthous ulcer, cessation of smoking and body weight loss.
It has been discovered that:
1. Epibatidine at approximately 1/100th the dose of nicotine (<10 μg/kg) mimicked nicotine-induced analgesia, hyperventilation, and tremor; with somewhat larger doses (>20 μg/kg), the tremor is followed by convulsion and death results from failure of respiration. Since the analgesic dose of nicotine is 10-50 times higher than its therapeutic dose (Reavill, in Nicotine Psychopharmacology, Wonnacott, et al., eds., Oxford University Press, pp. 307, (1990)), the satisfactory therapeutic effects may be achieved by the very potent nicotinic receptor agonist epibatidine at hundreds of nanograms to a few micrograms per kg. In this low dose range, epibatidine may not induce the undesired CNS effects that nicotine induces. When a higher dose of epibatidine is needed, these CNS responses to epibatidine could be avoided by a low starting dose, followed by a high dose a few minutes after the first dose.
2. The pretreatment with mecamylamine (a central nondepolarizing nicotinic blocker) at a very low dose completely blocked epibatidine-induced analgesia and other CNS responses.
3. The opioid antagonist naloxone and the α-2 adrenoceptor antagonist yohimbine blocked nicotine-induced analgesia (Tripathi et al., J. Pharmacol. Exp. Ther., 221: 91 (1982)), but did not antagonize epibatidine-induced analgesia.
4. Tachyphylaxis developed to epibatidine was much higher and longer than that developed to nicotine in both rats and mice.
I. Pharmaceutical Compositions
The pharmaceutical composition of the present invention may be administered to any host animal (for example, humans, equines, canines, bovines and other animals, and in particular, mammals) in need of treatment, by any suitable route including oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including, transdermal, subcutaneous, intramuscular, intravenous and intradermal). It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the condition and the active ingredients. The host animal includes In general a suitable dose for each of the above-mentioned conditions (e.g., Parkinson's disease, Tourette's syndrome, etc.) will be in the range of from about 0.1 to 20 μg per kilogram body weight of the recipient (e.g., a human) per day, preferably in the range of from about 0.5 to 2 μg per kilogram body weight per day and most preferably in the range of from about 1 to 2 μg per kilogram body weight per day. The desired dose is preferably presented as two, three, four, five, six or more sub-doses administered at appropriate time intervals throughout the day. These sub-doses may be administered in unit dosage form, for example, containing from about 0.05 to 5 μg, preferably from about 0.25 to 1.5 μg, and most preferably from about 0.5 to 1 μg of active ingredient per unit dosage form.
Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active ingredient of from about 0.2 to 30 ng/ml, preferably from about 1 to 15 ng/ml, most preferably about 2 to 10 ng/ml. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 0.2 to 50 μg/kg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.005 to 2 μg/kg/hour or by intermittent infusions containing about 0.1 to 5 μg/kg of the active ingredient.
While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation. The formulations of the present invention comprise the active ingredient, as defined above, together with at least one pharmaceutically acceptable carrier, diluent or excipient. Preferred formulations include those adapted for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Formulations of the present invention adapted for oral administration may be presented as discrete units such as capsules or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked providone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl-methyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
Formulation adapted for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations adapted for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or salicylate.
Formulations adapted for vaginal administration may by presented as pessaries, tampons, creams, gels, pasted, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations adapted for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be present in unit-dose or multi-dose sealed containers, for example, ampules and vials, and any be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately, prior to use. Extemporaneous injection solutions and suspensions any be prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations as those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
II. Evaluation of Biological Activity of Active Compounds
Methods for the determination of the specific cholinergic receptor activity profile for a selected compound is easily determined using known assays. For example, to determine which type or types of acetylcholinergic receptors a compound is interacting with, in vitro competitive binding assays can be performed using specific radioligands. A compound's ability to compete with a specific radioligand for receptor binding indicates an affinity for that receptor type. Radiolabelled nicotine (or cytisine) and quinuclidinyl benzilate are commonly used for nicotine and muscarinic receptor types, respectively. However, whether or not the compound is an agonist or antagonist is typically not determined by these assays.
To differentiate between agonists or antagonists, cell, tissue or animal-based in vitro or in vivo assays are typically employed. For nicotinic receptor ligands, one assay involves treating an animal with compound, then measuring a pharmacological activity associated with nicotinic receptor agonism, such tail-flick analgesia. If compound treatment resulted in analgesic activity, the compound is considered a nicotinic agonist. The compound's agonist activity should also be blocked by known nicotinic receptor antagonists. A similar protocol can be utilized if a cell-based assay, such as release of dopamine from striatal synaptosomes, is used.
If there is no nicotinic agonist activity, e.g. analgesia, in this example, after compound treatment, an effective dose of a known nicotinic agonist (such as nicotine) is subsequently given to the compound-treated animal. If the compound is an antagonist with the ability to block the effects of a known agonist, then the resulting analgesic activity would be less than that expected for the given dose of agonist.
Muscarinic agonists/antagonists can be characterized using appropriate muscarinic receptor-mediated in vitro and in vivo assays. Pharmacologic approaches can include, for example, include receptor-mediated mobilization of Ca+2 in cultured cells, depolarization of the rate superior cervical ganglion, or contraction of the longitudinal muscle myenteric-plexus preparation of the guinea pig.
Compounds which act as nicotinic receptor agonists are useful in the treatment of cognitive neurological and mental disorders, including Parkinson's disease, Tourette's Syndrome, Alzheimer's disease, attention deficit disorder, dementia, multi-infart dementia, vascular dementia, cognitive impairment due to organic brain disease including due to alcoholism and brain diseases, general problems with information processing, deficient regional cerebral blood flow and cerebral glucose utilization, psychiatric disorders (e.g., schizophrenia and depression), as well as other conditions such as analgesia, ulcerative colitis, aphthous ulcer, cessation of smoking, body weight loss and treatment of the symptoms of anxiety and frustration associated with withdrawal from other addictive substances, such as, cocaine, diazepam or alcohol. Nicotinic receptor agonists can also be used for veterinary purposes, including as respiratory stimulants, ectoparasiticides, and anthelmitics.
Compounds which act as nicotinic receptor antagonists are useful as ganglion-blocking agents, in the control of blood pressure in hypertension, in autonomic hyperreflexia regulation, in the control of hypotension during surgery and in the reduction of bleeding during operations. These compounds can also be used as stabilizing neuromuscular blocking agents which are extensively used as adjuvants in anesthesia for the relaxation of skeletal muscles, treatment for severe muscle spasms and ventilatory failure from various causes such as obstructive airway disorders. In addition, nicotinic receptor antagonists are useful as depolarizing neuromuscular blocking agents, for example, as skeletal muscle relaxants in endotracheal intubation or psychiatric electroshock therapy to prevent muscle and bone damage. Nicotine antagonists are also useful in blocking both the secretagogue and mitogenic effects of nicotine on cancer cells such as human small cell lung carcinoma. Finally, nicotine antagonists can be used as antidotes for curare/nicotine poisoning.
Muscarinic receptor agonists are widely used for ophthalmic purposes, for example, in the treatment of glaucoma to reduce intraocular pressure, applied alone or in combination with β-adrenergic blocking drugs or sympathomimetic agents, or for the treatment of accommodative esotropia. These agonists are also useful for one or more of the following indications: breaking adhesions between the iris and the lens; for the treatment of various disorders involving the depression of smooth muscle activity without obstruction (postoperative atony, congenital megacolon); in stimulating smooth muscle activity in the urinary and gastrointestinal tract; in reflux esophagitis, in the treatment of postoperative atonia of the stomach or bowel; for gastric retention following bilateral vagotomy; for congenital megacolon and combating esophageal reflux; in the treatment of urinary retention and inadequate emptying of the bladder postoperatively or post partum; and in the treatment of memory disorders and cognitive functions of Alzheimer's patients. The efficacy and side-effects of uscarinic receptors may be improved by optimizing their differential activity on various muscarinic receptor subtypes, e.g., M1 vs. M2/M3 receptors, as described by Showell, G. A., et al., Medicinal Chemical Research, 1993, 3:171-177.
Muscarinic receptor antagonists (antimuscarinic agents) are widely used in ophthalmology to produce mydriasis and/or cycloplegia. Selective M1 receptor antagonists are effective in treating peptic ulcer disease, and in the inhibition of gastric acid secretion. Antimuscarinic agents are also useful in treating increased tone or motility of the gastrointestinal tract, such as diarrheas, and in combating biliary and renal colics frequently in combination with an analgesic drug. Antimuscarinic agents, including quaternary ammonium compounds, are useful in treating obstructive pulmonary diseases such as chronic bronchitis or bronchial asthma. Cardioselective antimuscarinic agents are useful in treating symptomatic sinus bradycardia, e.g., in acute myocardial infarction, higher degree heart block and certain types of ventricular arrhythmias. Muscarinic receptor antagonists are also used in preoperative medication to counteract the vagal effects, to reduce excessive bronchial secretion, and to produce some sedation and amnesia. Centrally acting antimuscarinic agents are useful in the treatment of Parkinson's disease, by restoring the normal balance of cholinergic and dopaminergic neurotransmission in the basal ganglia, in the prevention of motion sickness, as a sedative, to relieve the symptoms of myasthenia gravis, in the antagonism of skeletal muscle relaxant effects of neuromuscular blocking agents, and in the treatment of poisoning by cholinesterase inhibitors such as those used in insecticides and chemical warfare. Such compounds are also useful to counteract anaesthesia effects, and in mushroom poisoning.
The clinical efficacy and safety of muscarinic receptor antagonists can be optimized by adjusting tissue selectivity, receptor subtype specificity and a balance of antagonism and agonism vs. different receptor subtypes, as well as by selective local (topical, aerosol, eye drop) or systemic administration of the drug.
The present invention will be further illustrated with reference to the following examples which will aid in the understanding of the present invention, but which are not to be construed as limitations thereof. All percentages report herein, unless otherwise specified, are percent by weight. All temperatures are expressed in degrees Celsius.
Female and male CD-1 mice (20-25 g) and male CD-1 rats (300-400 g) were obtained from Charles River Labs (Wilmington, Mass.). Rats were housed in groups of two and mice were housed in group of five. All animals had free access to tap water and chow pellets in a thermostatically-controlled room temperature (20� C.) on a 12 hour light/dark cycle.
Antinociceptive Activity of Epibatidine and Derivatives:
After the control values were measured, the antinociceptive activity of various epibatidine isomers and derivatives (n=5/group) was tested 5 minutes after s.c. injection.
The antinociceptive activity of epibatidine isomers and derivatives is summarized in Table 1. The d,l- (CMI-545), d- (CMI-488) and l-epibatidine (CMI-477) all showed very high potency with ED50 values of 10, 7 and 9 μg/kg, respectively.
Duration of Epibatidine- or Nicotine Induced Antinociception:
Duration of l-epibatidine- or nicotine-induced antinociception was assessed in mice by measuring antinociception at 2, 5, 10, 20 minutes after l-epibatidine (20 μg/kg, s.c.) or nicotine (5 mg/kg, s.c.).
As illustrated in FIG. 1, nicotine (5 mg/kg) and l-epibatidine (20 μg/kg) produced a decrease in responsiveness to radiant heat in the tail-flick test. A Friedman's analysis of variance test 15 revealed that the drug effect was significant (p<0.05). The onset of action was rapid with maximum antinociception occurring with 2 minutes for nicotine and 5 minutes for l-epibatidine. The duration of antinociception for l-epibatidine was about 20-30 minutes and for nicotine, 10 to 20 minutes.
Antagonixm of Epibatidine Antinociception in Mice:
Mide (n=7/group) were pretreated i.v. with either 0.9% saline or one antagonist (mecamylamine, hexamethonium, atropine, naloxone or yohimbine) 10 minutes before administration of l-epibatidine or nicotine at different doses. A control response (1.5-4 sec.) was determined for each animal before treatment and test latencies were assessed at 5 minutes after f-epibatidine administration (s.c., 5 ml/kg) or 2 minutes after nicotine (s.c., 5 ml/kg). The ED50 values were calculated using the PC software, GraphPad InPlot (ver 3.0).
Various drugs were tested for antagonism of epibatidine at a high dose (20 μg/kg) and the resorts are contained in Table 2. l-Epibatidine-induced antinociception, as measured by the tail-flick test, was completely blocked by pretreatment with the centrally active nicotinic receptor blocker mecamylamine at a low dose (1 mg/kg), but was not significantly affected by the opiate receptor antagonist naloxone up to 3 mg/kg. The quaternary nicotinic receptor blocker hexamethonium (3 mg/kg), which passes only poorly into the central nervous system (Taylor, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 18th Ed., Gilman et al. Eds., Pergamon Press, pp 166-186 (1990)) 1957), showed less potent antagonism of l-epibatidine than did the corresponding tertiary antagonist mecamylamine. Yohimbine (an α2 adrenergic antagonist) was less is effective, and atropine (M receptor antagonism) was inactive in antagonizing l-epibatidine antinociception.
A dose-response relationship was established in mice for both nicotine (FIG. 3A) and l-epibatidine (FIG. 3B) by measuring antinociception at the time of maximal effects. Two minutes after nicotine administration (s.c.), the ED50 value was found to be 1.4 mg/kg, whereas 5 minutes after l-epibatidine administration (s.c.) the ED50 value was determined to be 13.6 μg/kg. A dose of nicotine or epibatidine as high as the ED50 value produces tremors and sedation in most animals; with much higher doses (nicotine≧5 mg/kg, epibatidine≧20 μg/kg) tremors were followed by convulsions and death in some animals within 10 minutes after injection. Furthermore, in the animals pretreated with mecamylamine (1 mg/kg, i.v.) the dose response for either f-epibatidine or nicotine was measured. The potency ratio (i.e., ED50 value with blocker/ED50 value without blocker) for l-epibatidine and nicotine was found to be as high as 21.5 and 24.6, respectively (FIG. 2).
Also, the antinociception of d-epibatidine was completely abolished by the nicotinic receptor antagonist mecamylamine; but it was not affected by the opioid receptor antagonist naloxone (FIG. 3).
Effects of l-epibatidine and Nicotine on Respiration and Blood Pressure in Rats, and the Blockage Thereof by Mecamylamine:
Rats were anesthetized by sodium pentobarbital (50 mg/kg, i.p.) and body temperature of the animals was maintained by a Harvard homeothermic blanket (Harvard Apparatus, Edenbridge, KE) at 37� C. during these experiments. A polyethylene catheter (PE50) was inserted into the left common carotid artery. A polyethylene tubing (PE240) was inserted into the trachea and connected to a Fleisch 3.0 pneumotachograph (Whittaker, Blue Bell, Pa.), which was coupled to a Validyne DP45-14 differential pressure transducer (Validyne, Northridge, Calif.). Another PE 190 tubing was placed into esophagus. Transpulmonary pressure, as the difference between the tracheal and esophageal pressure, was detected by a Validyne MPXIIDP differential transducer. The mean blood pressure (MBP) and the heart rates (HR) were derived from the input signal of blood pressure. The respiratory parameters, including tidal volume (VT), respiratory frequency (RF), minute volume (VE), lung resistance (RL) and dynamic lung compliance (Cdys) were derived from the input signals of flow and the transpulmonary pressure. These data were captured by a Buxco LS-20 system with a PC 486 computer.
Rats (n=3-4/group) were pretreated with either 0.9% saline (1 ml/kg, i.p.) or mecamylamine (1 mg/kg, i.p.) 10 minutes before administration of l-epibatidine (10 μg/kg, s.c.) or nicotine (2 mg/kg, s.c.). Blood pressure, heart rate, and pulmonary functions were monitored during whole experiment.
After nicotine administration (2 mg/kg, s.c.) in anesthetized rats, the cardiovascular and pulmonary responses included hypertension or biphasic changes of blood pressure, depressed breath frequency, and increased tidal volume. Epibatidine (10 μg/kg, s.c.) mimicked these nicotine-induced changes. Mecamylamine (1 mg/kg, i.p.) also blocked l-epibatidine-induced respiratory responses and changes in blood pressure (FIG. 4).
Development of Tachyphylaxix:
The tachyphylaxis was assessed in mice by pretreatment with either l-epibatidine (15 μg/kg s.c.) or nicotine (5 mg/kg s.c.) at either 10 minutes, 3 or 16 hours (N=7/group) before a secondary injection. The mice were tested for antinociception 5 minutes after epibatidine administration and 2 minutes after administration of nicotine.
The animals receiving nicotine twice at 3 hour intervals showed no tachyphylaxis, whereas those receiving l-epibatidine at both 3 hour and 16 hour intervals developed tachyphylaxis (FIG. 5).
TABLE I__________________________________________________________________________Analgesic Effects of Epibatidine and Derivativesin the Tail-Flick Assay in Mice__________________________________________________________________________ ED50 value at 5 minutesCompound Dose Range (μg/kg, s.c.) (μg/kg)__________________________________________________________________________CMI-488 5-50 7(d)CMI-489 10-50 9(racemic)CMI-477 5-50 9(l)CMI-545 5-50 10CMI-526 50-200 127CMI-495 100-500 285CMI-492 500-1000 726__________________________________________________________________________STRUCTURES OF TEST COMPOUNDS__________________________________________________________________________ ##STR4## ##STR5## ##STR6## ##STR7## ##STR8## ##STR9## ##STR10##__________________________________________________________________________
TABLE II______________________________________Antagonism of epibatidine antinociception in mice Dose % MPEDrugs (mg/kg) mean SE P value*______________________________________0.9% NaCI 1 95 3mecamylamine 1 4 2 <0.001hexamethonium 3 50 18 <0.05naloxone 3 82 13 <0.05yohimbine 3 69 17 <0.05atropine 3 94 6 <0.05______________________________________ * As compared with vehicle (0.9% NaCl) effect.
The present invention has been described in detail, including the preferred embodiments thereof. However, it will be appreciated that those skilled in the art, upon consideration of the present disclosure, may make modifications and/or improvements on this invention and still be within the scope and spirit of this invention as set forth in the following claims.
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Peanut Butter Banana Chocolate Chip Cookies
By thesavvykitchen on December 19, 2012
Here's another awesomely delicious cookie recipe that anyone would love to receive in a cookie swap or as part of the dessert line. I made them a little healthier by using natural peanut butter and light butter, and they were nothing short of delicious.
The banana makes these cookies very moist and the subtle peanut butter paired with the chocolate chips is just divine. I know I'm taunting you with the triple-threat combination, so you should probably do yourself a favor and just go make these yourself. And don't forget to share. Enjoy!
- 2 cups plus 2 tbsp. all-purpose flour
- 1/2 tsp. baking soda
- 1/4 tsp. salt
- 8 tbsp. light unsalted butter, melted and cooled
- 6 tbsp. natural creamy peanut butter, melted and cooled
- 1 cup loosely packed brown sugar
- 1/2 cup granulated sugar
- 1 egg yolk
- 2 tsp. vanilla extract
- 1 1/2 ripe medium bananas, mashed
- 1 cup milk chocolate chips
Preheat oven to 325 degrees F.
Mix the flour, salt and baking soda in a bowl and set aside.
In the bowl of a stand mixer, whisk together cooled peanut butter and butter with both sugars until combined. Whisk in egg yolk and vanilla extract until smooth. Add in the mashed banana and mix until combined.
Gradually add in the dry ingredients, mixing just until dough forms. Fold in chocolate chips with a spatula.
Shape the dough into the size of a golfball and place on a nonstick baking sheet about 2 inches apart from each other. Slightly pat down each ball of dough.
Bake for 10-12 minutes, until the edges are golden and the middles are puffy – do not overbake! Let cool completely and then store in an air-tight container.
Source: The Savvy Kitchen
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|Alcohol and meds
Mar 27, 2002
I never miss a dose of Combivir -- so adherence is not a problem. (I'm taking AZT and 3TC as PEP, 11 does so far.) But occasionally I'll take the the drug on a relatively empty stomach with several (3 or 4) alcoholic drinks. I'm aware of the potential for toxicity and liver/pancreas problems. What I'd like to know is whether alcohol reduces or renders ineffective, in any way, the antiretroviral activity of these drugs. PLEASE answer, I'm scared.
| Response from Dr. Boyle
Moderate amounts of alcohol should not affect the effectiveness of these medications, unless it makes you forget to take them.
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Gathering multitudes of alliums- onions, chives, and scallions to gently flavor this herbalicious dip. I chose to avoid the strongest of the family, garlic.
Who wants to share a strong sulfury dip at a Superbowl party?
Creamy, flavorful but low fat, pale beautiful green, this combination of Alliums and White bean dip is perfect for Superbowl!
Feel free to change out the herbs to your personal favorites. I especially love sorrel in the summer time for its lemony tang, but in the depths of winter, my thoughts turn to the Allium family.
The Alliums family, those fragrant cooking standards from chives to garlic, from scallions to onions that thrive in the fall and winter. So many of them store well, providing a wonderful winter source of Vitamins A and C, with a big dose of calcium and iron.


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New Products
Red Hat has released a new distribution of Linux, RHS Linux. RHS Linux comes on CD-ROM only at this time, and features automated installation and X configuration, simplified system management tools, package installation and un-installation tools, and documentation. Source for all the binary packages is included in the same package format used to install the binary packages. RHS Linux complies with the Linux FSSTND, the standard that defines the location of most files on Linux systems, allowing you to install any FSSTNDcompliant binary package on your system without conflicts.
Red Hat Software can be reached at Red Hat Software, P.O. Box 4325, Chapel Hill, NC 27515; phone (919) 3099560; or email@example.com.
Soft*Star s.r.1. has released a Linux version of NetEye, a network management system based on OSF/Motif, SNMP, and a relational database. NetEye has very powerful support for monitoring networks and provides an intuitive graphical user interface that allows relatively inexperienced network administrators to effectively manage networks. It includes management of trouble reports, active network monitoring, reactive SNMP trap handling, and extensive reporting.
Soft*Star can be reached at Soft*Star s.r.1., Via Camburzano 9, 10143 Torino, Italy; +39 11 74 6092; fax +39 11 74 6487.
VersaSoft has released dBMAN, a dBASE III+ compatible DBMS, for Linux. It includes ad hoc query and edit capability, a report generator that does not require programming, scrollable windows (using termcap with color support), multi-dimensional arrays, data encryption and protection at the field level, source compatibility with dBASE III+ applications, extensions to dBASE III+ that are completely compatible over the more than 30 platforms supported by dBMAN, and a source-level debugger, yet requires less than 2MB of disk space to install.
VersaSoft can be reached at VersaSoft Corporation, 4340 Almaden Expressway, Suite 110, San Jose, CA 95118; phone (408) 723-9044; or fax (408) 723-9046.
Mountain Math Software has just released a new DSP environment, licensed under the GNU General Public License. ObjectProDSP allows you to create, test, and run DSP networks, and it can support some DSP hardware. It includes approximately 400 pages of documentation and validation test suites. ObjectProDSP is designed to create self-documenting projects. This is demonstrated by the fact that much of the documentation that comes with ObjectProDSP is generated in this way.
ObjectProDSP can be downloaded via ftp from tsxll.mit.edu in /pub/linux/packages/dsp, and from sunsite.unc.edu in /pub/Linux/devel/opd.
Mountain Math Software can be reached at Mountain Math Software, P.O. Box 2124, Saratoga, CA 95070; phone (408) 353-3989; or firstname.lastname@example.com.
ABS has ported their Metropolis Applications Environment to Linux. MAE integrates a DBMS with a character-mode windowing system called "flip" and a personal organization manager called "Assistant Plus" which integrates e-mail, phone message taking, scratch pad, appointment scheduler, to-do lists, and a profile list manager.
Alpha Base can be reached at (213) 850-6577; fax (213) 876-0986.
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Discovery Consumer Products has expanded its partnership with Wild Republic, part of K&M International, to launch new plush lines across several of its brands.
SCS Direct has laid a new line of Animal Planet-branded Hatch 'Ems eggs that feature animals that grow out of their shell when placed in water.
Discovery Consumer Products has partnered with Cartamundi for a new range of card games based on the Animal Planet TV series "Too Cute."
Discovery Consumer Products has added two new licensees for Animal Planet- and Shark Week-branded toys, puzzles and craft sets.
Discovery Consumer Products is currently exploring licensing and brand extension opportunities for its core properties.
Animal Planets and its R.O.A.R (Reach Out. Act. Respond.) fourth annual matching campaign kicks off with five returning and two new partners.
This month, Discovery Communications is unveiling its new division–Discovery Consumer Products, which unites the company's global licensing and merchandising businesses under one unit.
Discovery Communications has launched a new standalone app "Real Scary Spiders," in partnership with Animal Planet.
Discovery Communications licensees are showcasing a range of new apparel offerings featuring the network's top shows at MAGIC.
Discovery Communications is displaying new product for the Discovery Kids, TLC, Animal Planet and Discovery Channel brands at Toy Fair this week.
©2015 ADVANSTAR COMMUNICATIONS INC. All rights reserved.


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Select Local Merchants
Tango by The RiverRead MoreTango by the River is Northern California's premier venue for authentic Argentine tango. We teach tango on Tuesdays, Thursdays, and Fridays, plus we host a tango practica every Friday night and tango dances (milongas) every 2nd & 4th Saturday. We teach the real tango--the Argentine tango. It's sexy, passionate and fun!128 J StSacramento, CA US
Midtown Stomp Swing DancingRead MoreBusting a move you've never busted before—be it a contemporary ballet move, a jazzercise move, or a well-coordinated move to a nicer part of town and away from that mouthy opossum that keeps opening your mail—is a great way to get exercise, learn a new skill, and meet new and graceful friends. At Midtown Stomp, partners are encouraged to rotate, making the lessons as social as the open dance to help dancers learn new moves and catch the dance bug. Live music during the open dance will be provided by Phat Cat Swinger, a Hasselhoff-approved band that has toured the country and performed with Big Bad Voodoo Daddies, Royal Crown Revue, Cherry Poppin' Daddies, and The Coasters.2719 K StSacramento, CA US
Contemporary Dance ConservatoryRead MoreDirector Lena Logan already has a proven track record in the arts, racking up accolades as an actress, model, and Broadway dancer. Now, thanks to her work at Contemporary Dance Conservatory, she can add teacher to her already-sterling resume. Lena trains students based on their individual needs, strengths, and skills, sharing honest tutelage in ballet and contemporary styles that has helped former students gain admittance to the likes of NYU, Alvin Ailey, and Julliard. Students also display their skills in company productions as well as competitions that always seem to be held during a slow-motion rainstorm in a wind tunnel.213 26th StreetSacramento, CA US


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Man in Santa Suit Robs Bank During Santa Claus Convention!
A San Francisco bank was robbed by a man in a Santa suit. Then he walked out of the bank and onto the street where EVERYONE ELSE WAS DRESSED AS SANTA!
A San Francisco bank was robbed by a man in a Santa suit. Then he walked out of the bank and onto the street where EVERYONE ELSE WAS DRESSED AS SANTA!
My wife loves making holiday goodies and it's one of my favorite parts of Christmas. But we'd never think of making our own candy canes. Turns out for good reason! The skill and time involved is incredible! One of the steps requires a 2,000-lbs metal table needed to diffuse the heat from the 300-degree boiling sugar!
My Christmas vacation starts tomorrow. So I picked up a few things from the store for some "holiday projects." Want to see what I made?
A top UK newspaper polled adults on their favorite toys from the past 50 years. The list is pretty comprehensive! How many of these did you own?
Have a guitarist in your family? Don't know what to give them for Christmas? Here are some ideas to help get you started! These are from a guitarist, in no particular order, and are guaranteed to be successful
How to store wrapping paper so it doesn't unwind, Christmas pancakes, and a plastic bread clip can save your packing tape!! GREAT IDEAS!
OK, why have we been doing it WRONG all these years?? This so fast and amazing that two presents are wrapped to perfection in just 29 seconds in this video!!!
Don't end up paying more for postage than the gift! Know your shipping dates for the 2014 holidays! Today is your last day to ship standard for USPS!
We all know Santa Claus is real -- and Smithsonian magazine doesn't disagree -- but it claims his appearance was created by Coca-Cola.
Yesterday I blogged about my Silver Streak sled I got in the 2nd grade and I still have in my garage. What Christmas presents from your childhood have you held on to, and why?
Ugly, dorky and just plain overboard! Ugly Christmas sweaters are in again this year and here's how to make your own! If there's an ugly Christmas sweater contest at your work...YOU'LL WIN! OH, and today is National Ugly Christmas Sweater Day (true)!
The land of the rising son is also the land of folded paper art. They also love minimalism and simplicity. Add those cultural traits together and you get a method for gift-wrapping presents that is incredibly simple and efficient! I've been wrapping like a sucker for years! Watch this!


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Adopt, rescue or buy puppies, kittens and more in Dallas!
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OPHELIA Tuxedo Cat
3 days ago in Caddo Mills, TX
DOB 2/2011 Pretty Ophelia was in a family way and found herself at animal services with Oscar, Olivi...
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Fat Boy was an owner release along with Bandit (another cat on this site). The owner had to move and...
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Wadena crowns its 2009 pageant royalty
Cassondra Behl knew she was capable of winning the 2009 Miss Wadena pageant, but it was still a shock when the tiara was placed on her carefully coiffed curls.
"I couldn't believe that I actually won," the petite 17-year-old said the Monday after her big win.
Behl recalled the moment she heard that, yes, she gets to wear the name of her town as her title for the next year.
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Gillum House Bed & Breakfast
No availability found through our partners. Please contact the business directly or check some of our recommended alternatives.
How has this b&b rated in the past?
- Continental Breakfast
- Free High-Speed Internet
- Business Services
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- Kids activities or Babysitting
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Adventure to the Blue Ridge Parkway
... started dialing hotels in the area. Problem was we were speaking with a central booking agent not from the area or from this country for that matter. We luckily got the last room at a Comfort Inn near the highway just before a lady from Canada walked in with 6 kids. We paid dearly for that room on a Saturday night during UWV football season. There was a restaurant within walking distance and a convenience store to buy a much needed adult, cold ...
Baptism by fire and water.
... but it was mercifully brief and we felt rather smug. And then about an hour from the warm welcome of the "Angel Band Farm B&B" it started properly. It was heavy, intense – biblical even, to match the Philippi theme! I swear that there was a fellow off to the left loading his cows into an ark. And then the directions failed and we were lost and….we stopped to ask for help and there was a big scary dog and no people (I think the dog had eaten ...
Travel and Chill
... has the time gone? It's hard to believe the end of our trip is hours away. Thanks Steve for a flawless trip...all of the reservations were in place, the activities so memorable and the sites we saw will live in our memories forever. The time together as a family, traveling around the US, gives us a special bond. Just FYI-Steve ...
Day 37 - The Final Stretch
... it was 3:30 and we wanted to watch the USA soccer (football) game at 4:00. We found a Buffalo Wild Wings right off the exit, so we were happy until the USA lost.
Tomorrow morning we will complete the final leg to Blacksburg.
On a side note, it was a year ago today that I retired. Since then, we have driven over 11,000 miles in the RV, and visited Virginia, West Virginia, Maryland, Pennsylvania, New ...
Before the Trip (Ashley)
... but, even when I went to Costa Rica, I have never had to speak to everyone I know in Spanish! Emily and I have decided to speak Spanish to each other, which will probably be the most strange experience. No matter what happens, I am truly excited to have my sister by my side. I know that together, we can conquer anything (lame, I know). I hope that we spend a lot of time bonding, because there is no one else I would rather go with. Spain, here I come! ...


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text: Community featured forum posts Ask a question to the Ellicott City, MD Community 60th annivesary party (Catonsville, MD)(127 views / 1 posts) Last Post by Guest posted November 8, 2014 What are ideas for entertainment for a company picnic?(71985 views / 111 posts) Last Post by Guest posted 7 days ago A Birthday Isn't A Birthday Without....(19130 views / 46 posts) Last Post by posted 8 days ago The First 10 Steps for Wedding Planning(29154 views / 34 posts) Last Post by CRSocials posted February 19, 2015 What's the BEST piece of wedding advice you've ever gotten/heard?(8252 views / 22 posts) Last Post by djfur1301382 posted February 9, 2015 start a new discussion see more posts


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CH Mountain Star Bodacious One WC "BO" just finished his AKC title. Tough in Labs he got a mojor by beating over 50 other Labs. His first major came when he was 8 months old he is now over 3. Bo is now going to work on his JH and Obedience Title.


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Park Hotel Drevny Grad - Lviv
Gamaliivka - Lviv1-877-662-6988
24-hour room service and free breakfast are just some of the great amenities you'll find at Park Hotel Drevny Grad, an excellent choice for those looking for business-friendly hotels in Lviv that are also in a provincial park.
This 3-star Lviv hotel offers a hair salon. If you are visiting Ukraine on vacation or for business, make sure to take some time to relax as you will find a sauna on site, so make the most of it! Multilingual staff are available at the front desk 24 hours-a-day and can provide tour/ticket assistance.
The lobby offers a fireplace, TV and free newspapers. Free Wi-Fi is provided so you can check your in-box whenever you like. Planning a meeting? This hotel has 2 meeting rooms, as well as a business center. Other amenities include gift shops/newsstands and a garden.
Stayed for one night with 2 children: the quitness of the cottage and wonderful te...Venere Guest, Ukraine
These reviews have been left by customers who actually stayed at this hotel
Check Availability at Park Hotel Drevny Grad
Breakfast at Park Hotel Drevny Grad
A free buffet breakfast is available between 7:00 AM and 11:00 AM.
Facilities at Park Hotel Drevny Grad
- Business Center
- Conference room
- Sauna
- Dogs allowed
- Hairdresser
- Room service - 24 hour
- Gift shop
- Garden
- Pets accepted
- Free parking
- Multilingual staff
- Newspapers
- City tour
- Front desk - 24 hour
- Internet/Email services
- TV Lounge
- Restaurant/Dining
Know before you go
- If you require a visa to enter the country, your hotel may be able to help with the supporting documents needed to obtain one. To learn more, you can reach out to the hotel via the contact details included on your booking confirmation. The hotel may charge for this assistance, even if you end up cancelling your reservation. All arrangements are solely between the hotel and yourself.
Check-in: between 1:30 PM and 2:00 PM.
Check-out: before 12:30 AM.
PolicyExtra-person charges may apply and vary depending on hotel policy.
Government-issued photo identification and a credit card or cash deposit are required at check-in for incidental charges.
Special requests are subject to availability upon check-in and may incur additional charges. Special requests cannot be guaranteed.
Park Hotel Drevny Grad reviews
- July 2014
- Venere Guest
- Family with young children
- Ukraine
Stayed for one night with 2 children: the quitness of the cottage and wonderful territory with a lot of trees and flowers was exactly what we needed after 8-hour journey. Evening in restaurant was also very nice. Children appreciated very big playground.
Park Hotel Drevny Grad reviews by TripAdvisor
Room Details
Book your business-friendly accommodation at the 68-room Park Hotel Drevny Grad. Rooms open onto balconies. Televisions in each room offer entertainment at the end of a long day. Business travelers will have access to free wireless high-speed Internet access as well as desks and phones during their Lviv visit.
Bathrooms are outfitted with slippers and complimentary toiletries. Coffee/tea makers and complimentary bottled water are supplied in each room to facilitate basic travel needs.
Accommodation Services
- Telephone
- Extra beds
- Coffee and tea maker
- Desk
- Wireless Internet access
- Terrace/Balcony
Distances from Park Hotel Drevny GradHigh Castle - 7.9 km / 4.9 mi
Dominican Church - 8.5 km / 5.3 mi
Pharmacy Museum - 8.6 km / 5.4 mi
Armenian Cathedral - 8.7 km / 5.4 mi
Church of the Transfiguration - 8.7 km / 5.4 mi
Lviv City Hall - 8.8 km / 5.4 mi
Market Square - 8.8 km / 5.5 mi
Lviv State Natural History Museum - 8.9 km / 5.5 mi
Boim Chapel - 8.9 km / 5.5 mi
Lviv Theatre of Opera and Ballet - 8.9 km / 5.5 mi
Latin Cathedral - 8.9 km / 5.5 mi
Taras Shevchenko Monument - 9 km / 5.6 mi
Museum of Banking Technology - 9.2 km / 5.7 mi
Potocki Palace - 9.3 km / 5.8 mi
Lviv Art Palace - 9.3 km / 5.8 mi
The preferred airport for Park Hotel Drevny Grad is Lviv (LWO-Lviv Intl.) - 14.8 km / 9.2 mi.
Distances are calculated in a straight line from the property's location to the point of interest or airport and may not reflect actual travel distance.
Distances are displayed to the nearest 0.1 mile and kilometer.
Transportation services Park Hotel Drevny Grad
- Free parking
We have the accommodation you need, all over the world
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- • Ivy Guest House - Edinburgh, United Kingdom
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- • Grande Prairie Hotels, Canada


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Another name for a stationary-magnet, moving-coil meter is the movement.
D'Arsonval movement is a basic analog meter movement which consists of a permanent magnet, a rotating coil in the field of permanent magnet and an indicating needle attached to the rotating coil. The moving coil meter is also called D'Arsonval movement because the precision-type jewel bearings known as D'Arsonval movement are used for mounting the rotating coil in the moving coil meter.
Chegg is one of the leading providers of homework help for college and high school students. Get homework help and answers to your toughest questions in math, calculus, algebra, physics, chemistry, science, accounting, English and more. Master your homework assignments with our step-by-step solutions to more than 3000 textbooks. If we don't support your textbook, don't worry! You can ask a homework question and get an answer in as little as two hours. With Chegg, homework help is just a few clicks away.


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1993 Mazda RX-7This is an immaculate car. I moved from the West coast and I want to have some thing daily driver not fancy... More
1976 Alfa Romeo Alfetta GT1976 Alfa Romeo Alfetta GT model in mint conditionCompletely repaint - white exterior with a Black interiorUpgraded front and rear... More
1990 Buick Reatta1990 Buick Reatta model in mint conditionLight Grey-Blue metallic exterior - beautifulHand-made with original Book and Signature of fabricatorsBrand new front HeadlightsBrand... More
1974 MG MGB III 2 Door Roadster1974 MG MGB III 2 Door Roadster model in mint conditionIt is time to get out of your... More
1965 Ford Mustang1965 Ford Mustang 289 Original model in great conditionTurquoise metallic exterior with a Black interiorEquipped with an 8-Cylinder RWD gas and a... More
1980 Chevrolet Corvette1980 Chevrolet Corvette model in mint conditionBlack metallic exterior with a two-tone Black and Brown leather interiorThis is a nice running driving... More
1967 Chevrolet El Camino1967 Chevrolet El Camino model in mint conditionEquipped with a 350 cubic inch V8 Small Block gas with a 350 Automatic... More
1988 Chevrolet K5 Blazer1988 Chevrolet K5 Blazer model in mint conditionTan metallic exterior with a matching Tan interiorHas been rebuilt from 'Bumper-to-Bumper' with All... More
1974 Chevrolet Camaro Z281974 Chevrolet Camaro Z28 model in mint conditionBrand new WhineBored 30 over9.5 to 1 Compression Ratio100 miles on the EngineTurbo transmission3.73... More
1966 Ford Mustang1966 Ford Mustang model in mint conditionRed metallic exterior with a Custom interiorEquipped with a Straight 6-Cylinder gas and an Automatic transmissionCurrently... More
1923 Ford Model TClassified as a 1923 Ford Model T Kit car in mint conditionCandy-Apple Red metallic exterior with a matching Red interiorEquipped with... More
1972 Chevrolet Chevelle Concours Estate1972 Chevrolet Chevelle Concours Estate model in mint conditionSilver metallic exterior with a Black top plus a matching Silver interiorEquipped... More
1971 Chevrolet Nova1971 Chevrolet Nova model in mint conditionMust sell!This is one tricked out Chevrolet Nova as wellBlack satin exterior with a matching Black... More
1963 Lincoln ContinentalPearl White 1963 Lincoln Continental in great shape. Features - 4 DoorV8 AutomaticSuicide DoorsPower WindowsFront Disc BrakesElectricFuel PumpFactory ACNew CarpetNew Headliner22 Inch... More
1934 Chevrolet DA Master1934 Chevrolet DA Master in mint condition3-Window Coupe model with a Steel bodyGlass finderSide Running boardsSplash ApronDeck LidBoxed frameTCI front with... More


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The Clayton Building Committee will meet for the first time Tuesday, Aug. 27 at 6:30 p.m. at Clayton Town Hall.
Clayton Town Hall is located at 414 Main St. in Clayton.
The purpose of the meeting is to review the police station expansion.
Your privacy is important, read our privacy policy.


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The 8.8-magnitude earthquake that rocked Chile over the weekend damaged homes and killed more than 700 people so far, but Chileans living in Queens said they were grateful it was not worse.
Several immigrants from the South American nation gathered at the San Antonio Bakery in Astoria and were glued to the cafe's television set, which was playing round-the-clock Chilean news.
Ivan Rodriguez, a first-generation Chilean American who lives in College Point, said that although he knows there are millions of people who have been displaced by the disaster, he was confident the country would be prepared to handle the aftermath, since it has been hit with other quakes over the last 25 years.
"This isn't anything new to Chile," said the 30-year-old, who had gotten in contact with some of his family who live there. "Chile is one of the most developed countries and the response will be quick."
The quake, the most massive recorded in the history of the nation, hit early Saturday morning near the city of Concepcion and sent shockwaves across the Pacific Ocean. Some 1.5 million homes were affected by the rumblings, according to the Associated Press and BBC, and there were several powerful aftershocks Sunday and Saturday.
The nation experienced 8.0-magnitude earthquakes in 1985 and 1995.
Chilean immigrant Italo Baroni, 45, of Brooklyn, who was with his niece, Soledad Marambio, and her friends at the bakery, said residents are fully aware they are living on a volatile fault line and are prepared for the worst at an early age.
"You are taught when you are young how to deal with earthquakes," he said.
Marambio, 33, concurred and said the disaster was not as severe as January's earthquake in Haiti. She said the Chilean roads and buildings were built to handle quakes and the government has the resources to handle the aftermath.
"It could have been a lot worse," the student said.
Another advantage Chileans had was communication, according to those gathered at the bakery since the phone and Internet systems came online within 24 hours, according to Chilean nationals living here.
Susana Rojas, a 26-year-old Chilean who lives in Astoria, said that although she did not get in direct contact with her friends and family, she was able to get in touch with them through Facebook, Twitter and text messaging.
"It looks like it's the only way to connect with them," she said as she kept watch for updates on her iPhone.
Reach reporter Ivan Pereira by e-mail at email@example.com or by phone at 718-260-4546.
©2010 Community News Group
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11:18 am
Wed September 26, 2007
How to Save Your Life #051
Albany, NY – Dr. Stieg welcomes Jodi Sleeper-Triplett, a Master Certified Coach for the treatment of AD/HD. Attention-Deficit/Hyperactivity Disorder affects millions of children and adults. Dr. Stieg asks about the different types of AD/HD and what this diagnosis means for everyday life. Jodi offers advice on how to set structure, provide support and help implement strategies for dealing with AD/HD.


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Our new devotional "If God Loves Me, Why Did I Lose My Job?" explores the struggle of unemployment. Sign up here.
45:4 servant. See notes at 20:3; 41:8; 42:1.
chosen. See note 14:1.
name you. As God's "shepherd" (44:28) and "anointed" (v. 1), Cyrus has a title of honor.
you do not know me. Cyrus remained an unbeliever.


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I'm an old geezer, but I don't get into the trap of reminiscing much. There's not that much good to look back on. But this forum at least gives us old folk a way to pass on what we've learned over the years to the younger people. So many of them are now growing up in a world devoid of morals, where opportunity to "get ahead" is seldom encountered. I hope us old folk can instill into the younger Americans the values and hopes we had in our youth, and encourage them to fight off the ever-increasing infringing on our God-given rights of freedom and dignity as human beings.
somedays, like these of lately, i have felt very old and tired. sure sucks to get old!
Texan By Birth & Choice
Like it or not, when the chips are down and lives are at stake, an armed citizen can be the "first responder." People who dont like guns invariably rely on people who have guns when their lives are in danger.
"A well regulated Militia, being necessary to the security of a free State, the right of the people to keep and bear Arms, shall not be infringed." 2nd Amendment to the Constitution of the United States
Practice does NOT make perfect. Practice makes permanent. Only perfect practice makes perfect.
"Give me strength and wisdom to accept the things I can not change".!
Patients my friend , all things may pass.!
A reporter was interviewing a 104 year-old woman: "And what do you think is
the best thing about being 104?" the reporter asked.
She simply replied, "No peer pressure."
Just before the funeral services, the undertaker came up to the very elderly
widow and asked, "How old was your husband?"
"98," she replied. "Two years older than me."
"So you're 96," the undertaker commented. "Hardly worth going home, isn't
Somebody has to speak for these people. Y'all got on this boat for different reasons, but y'all come to the same place. So now I'm asking more of you than I have before. Maybe all. Sure as I know anything, I know thisthey will try again. Maybe on another world, maybe on this very ground swept clean. A year from now, ten? They'll swing back to the belief that they can make people...better. And I do not hold to that. So no more runnin'. I aim to misbehave. Mal Reynolds Serenity/Firefly


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the car wont say anything. The alarm light will etheir stay on or not. It wont flash as usual. The battery had a bad cell in it so I replaced it with a new one, but to no evail. I notice that I can nolonger open the drivers door with the key or the keyless entry. I have to open the door from the inside. would this mess up the alarm system?
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1990 Lincoln Town Car Question: the actual year of my towncar is 1989.
earlga2, Fort Lauderdale, FL, November 05, 2009, 15:20
1 Answer
Answer #1dandd November 05, 2009, 16:03Master
A bad battery can cause the alarm to need a re-set or more. It may be that your alarm failed. This can be a tough situation, because a factory alarm is really hard to bypass and, it is next to impossible, I find in my every day shop experience, to find Ford parts that are more than about 12 years old from the factory. They stop making them after about 10 years, which I think is horrible. I often have to have cars donated for Smog Repairs in Calif, just because there are not factory parts and the after market does not make them, say like EVAP parts. I would try a good alarm shop and see what they can come up with, maybe they know how to get around the factory stuff.
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