Cigarette smoking is the number one health problem accounting for more illness and deaths in the US than any other factor. Elucidating the mechanism of action of nicotine (NIC) is of importance in understanding the initiation and maintenance of tobacco smoking behavior. Over the past 10 years, there has been a substantial increase in the understanding of brain nicotinic receptors at the molecular level. The structural and functional diversity of these receptors has stimulated interest in the development of subtype selective agonists. Surprisingly little attention has focussed on the development of subtype selective antagonists. The proposed research will determine the structure activity relationship (SAR) of a new class of nicotinic antagonists, i.e., pyridine-N substituted NIC analogues. Preliminary results demonstrate that N-octylnicotinium iodide (NONI) is a potent and selective antagonist of NIC evoked [3H]dopamine (DA) release. NONI has been prepared as a [3H]ligand (specific activity, 80 Ci/mmol) for determining the regional localization of the specific nicotinic receptor subtype involved in NIC evoked [3H]DA release. N-decylnicotinium iodide (NDNI), competitively and with high affinity binds to the [3H]NIC binding site, but does not inhibit NIC evoked [3H]DA release. These preliminary data demonstrate that pyridine-N substitution of the NIC molecule confers nicotinic receptor antagonist activity to these analogues, and moreover, suggests that NONI and NDNI are selective for different nicotinic receptor subtypes. The proposed research will test the hypothesis that SAR directed at the pyridine-N substituent will optimize the potency, efficacy, and moreover, nicotinic receptor subtype selectivity of this novel class of nicotinic receptor antagonist. Pyridine-N substituents to be studied include varying steric bulk and lipophilicity, alteration of C-2' chirality, and enlargement of the pyrrolidine ring to a piperidine ring. The rotameric preference about the C(3)-C(2') bond will also be determined by incorporating active antagonist molecules into a conformationally more rigid structure. Thus, the major goal of this proposal is to determine structural features of the novel NIC analogues that convert the NIC molecule from an agonist to an antagonist at specific nicotinic receptor subtypes. These subtype selective nicotinic receptor antagonists would be invaluable neuropharmacological agents for basic and clinical research.
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