The objective of the proposed multidisciplinary, multiuniversity research initiative is the development of nicotine acetylcholine receptor (nAChR) selective agonists and antagonists as potential therapeutic agents for nicotine addiction and other central nervous system disorders mediated by nAChRs. Novel analogues of the potent nAChR ligand, epibatidine will be synthesized and evaluated in vitro and in vivo as potential potent selective nAChR ligands.
The specific aims of the proposed work to achieve this objective are fourfold: 1) The efficient syntheses of (q)-epibatidine as well as natural (-)-epibatidine and (+)- epibatidine will be investigated to provide useful quantities of these rare compounds for study. In addition, useful enantiomeric intermediates will be generated from this study for use in concurrent structure activity relationship studies. 2) Novel analogues of epibatidine and hybrid molecules of epibatidine and potent nAChR ligands will be synthesized and tested in in vitro paradigms to systematically investigate the structural features associated with the molecular recognition by nAChRs in the brain. In addition, epibatidine and related-analogues will be evaluated at brain opioid receptors to establish receptor selective binding and clearly establish nAChR selectivity. 3) Novel analogues of epibatidine will be tested for functional agonist/antagonist activity at nAChR. This will be done by measuring the effects of these compounds on dopamine and norepinephrine release. 4) Selected potent active analogues will be employed in in vivo studies to investigate nAChR mediated analgesia to establish agonist or antagonist activity. Both central and peripheral nervous L system activity will be evaluated.
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