Although nicotine produces diverse pharmacological effects in the central nervous system, the most noteworthy of which is its addictive properties, relatively little is known regarding the mechanism by which it produces these effects. It appears that some, but not all, of nicotine's central effects are mediated via the cholinergic system. The nicotinic cholinergic nervous system has been reasonably well characterized in the peripheral nervous system which has prompted speculation that nicotine acts in a similar fashion in the brain. However, there is considerable evidence demonstrating differences between central and peripheral nicotinic systems. Interestingly, many of these discrepancies have arisen as a result of investigations with the nicotinic antagonists. One of the most intriguing aspects of the antagonists is that they do not bind to the central nicotine receptor. This observation, along with the fact that some antagonists block nicotine's central effects in a noncompetitive manner, is integral to our hypothesis that nicotinic agonists and antagonists interact with different receptors in the brain to produce their respective effects. In order to test this hypothesis, we propose to evaluate the structure- activity relationships of both nicotine and its antagonists to determine whether they are capable of sharing a common pharmacophore. Conformationally restricted analogs of nicotine, mecamylamine analogs and N-mustards of agonists and antagonists will be synthesized and evaluated for pharmacological potency in several behavioral assays. These analogs will also be evaluated in 3H-nicotine and 3H-mecamylamine binding assays to corroborate the in vivo findings. Molecular modeling studies will be carried out to determine whether it is possible for both agonists and antagonists to occupy a common pharmacophore. Behavioral, electrophysiological, and in vitro studies will also be conducted in order to identify the second messengers of the agonist and antagonist receptors. The studies should provide insight into the actions of both agonists and antagonists which will lead to a better understanding of the neural processes involved in nicotine's actions in the brain.
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