Because nicotine seems to produce a number of beneficial effects, presumably mediated via nicotinic acetylcholinergic (nACh( receptors, it is desirable to develop novel nicotinic agents that retain the beneficial effects of nicotine but that lack its toxic and undesirable aspects. Such agents could be of benefit in smoking cessation therapy, pain management, and the treatment of certain mental and neurological disorders. Our long term goal is the development of such agents. A more immediate goal is an enhanced understanding of neuronal nACh receptors and knowledge of how to design agents that will interact selectively with these receptors. To this end, we are attempting to define and investigate and pharmacophore for central nACh receptor action. A nicotinic pharmacophore, initially proposed in 1970, has been challenged and modified by us and by others. We currently believe that multiple pharmacophores are possible, and that different pharmacophores might even account for agonist vs. antagonist actions. Our present investigations can be broadly divided into two categories: development and validation of pharmacophore models, and exploitation of leads we have already developed. Specifically, we propose to a) explore what appears to be a new nACh receptor binding feature, b) evaluate a structure-based hypotheses regarding binding and functional activity, c) determiner whether or not structurally distinct ligands bind in a common manner at nACh receptors, d) investigate a series of agents that offers the prospect of possessing """"""""peripheral"""""""" analgesic activity, e) explore potentially selective nACh receptor ligands, and f) investigate the actions of bupropion optical isomers and metabolites, and to examine a role for dopamine in the nicotine-like effects of bupropion. Compounds necessary for these investigations will be synthesized. All compounds will be examined in radioligand binding assays at alpha4beta2, nACh receptors. Selected compounds, depending on their affinity (i.e., alpha4beta2 Ki<100 nM or Ki > 100 nM), will be examined in other binding assays and as agonists and antagonists in functional assays (e.g. antinociceptive activity, locomotor effects and body temperature using mice; drug discrimination studies with rats), following a specific protocols. Radioligand binding (and to some extent functional) data will be used to determine the validity of existing pharmacophore models and, if necessary to develop new models.
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