Synthesis and pharmacology of site-specific cocaine abuse treatment agents

Illicit use of cocaine continues to be major health problem in the United States and no effective pharmacotherapy exists for its abuse. The aim of this work is to address the problem by developing site-directed cocaine abuse treatment agents which will attenuate the addictive and highly pleasurable effects of cocaine mediated at the dopamine nerve terminals in the brain. Specifically, the purpose of the work described here is to synthesize compounds which interact with the cocaine binding site on the dopamine transporter and to preclinically evaluate them as potential therapeutic agents for abuse of cocaine.; The work described in this thesis is an extension of previous work on disubstituted bicyclo[2.2.2]octanes. In this work, trisubstituted bicyclo[2.2.2]octanes were synthesized. The installation of a potential third point of binding was investigated on this framework. Incorporation of a ketone functionality allowed for further elaboration of the structure with the focus of incorporating a benzoyl ester group in various regio- and stereochemical combinations, while maintaining the [2.2.2] bicyclic core. Incorporation of the ester group further increases the structural analogy with that of cocaine. In addition it provides insight into the 3-D spatial requirements of the cocaine binding site at the dopamine transporter. Selected compounds were studied for their effect on the dopamine transporter by measuring inhibition of [3H]WIN 35,428 binding and [3H]dopamine uptake. Measurement of the displacement of [3H]nisoxetine and [3H]paroxetine from the NE and 5-HT transporters are also reported to demonstrate transporter selectivity of the compounds.