Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-12-17
2000-06-20
Jarvis, William R. A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 3144
Patent
active
060778466
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
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 N.sub.M and N.sub.N receptor respectively).
Muscarinic receptors may also be divided into at least two subtypes, M.sub.1 and M.sub.2. In general, muscarinic cholinergic receptors with the pharmacological profile characteristic of the M.sub.1 subtype are found in autonomic ganglia and in the CNS, whereas M.sub.2 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.sup.+ and K.sup.+, 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
REFERENCES:
patent: 4835162 (1989-05-01), Abood
patent: 4910193 (1990-03-01), Buchheit
patent: 4940703 (1990-07-01), Baker et al.
patent: 4966916 (1990-10-01), Abood
patent: 4992436 (1991-02-01), Baker et al.
patent: 5104989 (1992-04-01), Cottrell et al.
patent: 5106853 (1992-04-01), Showell et al.
patent: 5124460 (1992-06-01), Humphrey
patent: 5128118 (1992-07-01), Carroll et al.
patent: 5219860 (1993-06-01), Chambers et al.
patent: 5227385 (1993-07-01), Caldwell et al.
patent: 5242927 (1993-09-01), Baker et al.
patent: 5242930 (1993-09-01), Baker et al.
patent: 5256671 (1993-10-01), Ladduwahetty et al.
patent: 5260293 (1993-11-01), Baker et al.
patent: 5288730 (1994-02-01), Baker et al.
patent: 5314899 (1994-05-01), Daly et al.
patent: 5324723 (1994-06-01), Baker et al.
patent: 5405853 (1995-04-01), Baker et al.
patent: 5426106 (1995-06-01), Kulagowski et al.
patent: 5432177 (1995-07-01), Baker et al.
patent: 5444074 (1995-08-01), Baker et al.
patent: 5451588 (1995-09-01), Baker et al.
patent: 5459270 (1995-10-01), Williams et al.
patent: 5461063 (1995-10-01), Kelleher et al.
Abstracts of Poster Presentations Nos. 1-97, "The Otto Loewi New Investigator Awards for 1995," Life Sciences, 56(11/12):1001-1050 (1995).
Adamus, et al., "Phase I Clinical Trials with WAL2014, A New Muscarinic Agonist for the Treatment of Alzheimer's Disease," Life Sciences, 56:(11/12):883-890 (1995) (Elsevier Sciences, Ltd., Editors).
Ainsworth, et al., "Alkyl-1,3,4-oxadiazoles," J. Org. Chem., 31:3442-3444 (1966).
Altenbach, H.J., et al., "7-Azanorbornadiene," Angew Chem. Int. Ed. Engl., 21(10):778 (1992).
Altenbach, H.J., et al., "Synthesis and Photoelectron Spectra of 7-Azanorbornadiene and Related Compounds. An Analysis with Fragment Orbitals," Chem. Ber. 124:791-801 (1991).
Badio and Daly, "Epibatidine, a Potent Analgetic and Nicotinic Agonist," Mol. Pharmacol., 45:563-569 (1994).
Badio and Daly, "Epibatidine. A potent analgetic and nicotinic agonist," FASEB Journal, 8(4-5):A875 (1994).
Baker and Saunders, "Central Muscarinic Ligands and Receptors," Ann. Rep. in Med. Chem. Chapter 4, 24:31-39 (1989).
Bansal, et al., "Influence of Lewis acids on the Diels-Alder reaction. Part I. An improved synthesis of 7-azanorbornadiene, 3-azaquadricyclaine, and azepine derivatives," Can. J. Chem., 47:2391-2394 (1969).
Barber, and Gottschlich, "Opioid Agonists and Antagonists: An Evaluation of Their Peripheral Actions in Inflammation," Medicinal Research Review, 12(5):525-562 (1992).
Barnes, et al., "Tiotropium Bromide (Ba 679 BR), a Novel, Long-Acting Muscarinic Antagonists for the Treatment of Obstructive Airways Disease," Life Sciences, 56:(11/12):853-859 (1995) (Elsevier Science, Ltd., Editors).
Bhattacharya, S.N., et al., "Friedel-Crafts Sulphonylation of Bis(trimethylsilyl)acetylene: a Useful Route to Aryl Ethynyl Sulphones," Organomet. Chem. Synth., 1:145-149 (1970).
Bittoun, "Recurrent aphthous ulcers and nicotine," Med. J. Australia, 154:471-472 (1991).
Bradley, "Frog Venom Cocktail Yields A One-Handed Painkiller," Science 261:1117 (1993).
Broka, C.A., "Total Synthesis of Epibatidine," Tet. Lett., 34(20):3251-3254 (1993).
Burgen, "The Background of the Muscarinic System," Life Sciences, 56(11/12):801-806 (1995) (Elsevier Science, Ltd., Editors).
Burke, et al., "Construction of a Molecular Shape Analysis-Three-Dimensional Quantitative Structure-Analysis Relationship for an Analog Series of Pyridobenzodiazepinone Inhibitors of Muscarinic 2 and 3 Receptors," J. Med. Chem., 37:3775-3788 (1994).
Carroll, et al., "3-Aryl-2-(3'-substituted-1',2',4'-oxidiazol-5'-yl)tropane Analogues of Cocaine: Affinities at the Cocaine Binding Site at the Dopamine, Serotonin, and Norepinephrine Transporters," J. Med. Chem., 36:2886-2890 (1993).
Chen, et al., "Synthesis of the Epibatidine Ring System from Pyrroles via Their Pentaammineosmium(II) Complexes," Am. Chem. Soc. Meeting, Denver, Colorado (Mar. 28-Apr. 2), 1993.
Christensen, et al., "Antinociceptive effects of the stereoisomers of nicotine given in
Biftu Tesfaye
Li Tongchuan
Qian Changgeng
Shen Tsung-Ying
Jarvis William R. A.
UCB S.A.
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