Cocaine dependence is a problem of national significance. A considerable effort has been expended in the study of its mechanisms of action. Notwithstanding, to date no cocaine pharmacotherapy has been approved by the FDA. The reinforcing properties and stimulant effects of cocaine are associated with its propensity to bind to the dopamine transporter (DAT). Tropane analogs are potent inhibitors of the DAT. Among the strategies utilized for the design of cocaine therapies is the development of compounds which bind to the same site. The 3-phenyltropanes have been prominent among these and structure activity relationship studies have largely focused on this series of cocaine analogs. The goal of this proposal is to design novel tropanes as potential pharmacotherapies for cocaine dependence.
The specific aims are to synthesize and evaluate biologically five classes of novel tropanes: 8-oxa-3-aryltropanes, 6- or 7-hydroxytropanes, 6- or 7-hydroxy-8-oxa-3-aryltropanes, 2,3-didehydro-8-aza- and 8-oxa-tropanes, and 6-or 7-hydroxylated 2,3-didehydro-8-aza- and 8-oxatropanes. Carefully selected compounds will be prepared and their inhibition of monoamine transport will be determined. Potent and selective compounds will be assayed for inhibition of dopamine uptake and those compounds which inhibit cocaine uptake with minimal effect on dopamine uptake will be subjected to behavioral studies. It is anticipated that these studies will lead to a disclosure of SAR on aspects of the tropanes hitherto uninvestigated.
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