Nicotine continues to be an important area of drug abuse research; however, most studies with nicotine receptors, indeed much of nicotine pharmacology, is limited to the use of a small handful of standard agents (e.g., nicotinoids such as nicotine, nicotine metabolites such as cotinine, noncompetitive nicotinic antagonists such as mecamylamine, nicotinic neurotoxins such as bungarotoxin), and/or (at least for structure-activity studies) has focussed primarily on the use of peripheral nicotine receptor preparations. Although such studies are obviously necessary, information gained from using the same small number of agents may be limiting in terms of understanding mechanisms of action, especially at the level of the central nervous system. This information is particularly restrictive with respect to formulation of structure- activity relationships and medications development/drug design. Something as basic as a 'nicotine receptor pharmacophore' for the central actions of nicotine has yet to be developed. It is fairly clear that in the not too distant past there was a lack of nicotinic agents, and lack of a common and reliable method whereby the central activity of these agents could be examined. With the advent of binding methodology and the availability of suitable radioligands, we can now address some important issues; however, a need remains for new nicotinic agents. We have already initiated studies by synthesizing compounds required to lay the necessary groundwork; we now wish to further extend these studies and to apply the results of this work. We propose to conduct a series of studies to identify and develop a central nicotine receptor pharmacophore, and to challenge/confirm binding hypotheses already developed in our laboratory. Specifically, we will: (a) synthesize specific nicotine partial-structures and related compounds designed on the basis of the first ever QSAR investigations conducted on nicotinic agents, (b) synthesize conformationally-restricted nicotinic and related agents to test distance hypotheses, (c) conduct molecular modeling studies and utilize other computational (e.g., QSAR) methods to aid in developing and refining a central nicotine receptor pharmacophore, (d) utilize radioligand binding data as a primary source of input to develop/refine the pharmacophore model, and (e) obtain drug discrimination (nicotine-trained rats), antinociceptive (mice), and locomotor (mice) data on target compounds as a measure of functional activity. The long-term goal of this work is to determine if different nicotine receptor subunits will exhibit different pharmacophore requirements and to use such information to develop subtype- selective nicotinic ligands.
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