Synthesis and Pharmacology of Potential Site-Specific Therapeutic Agents for Cocaine Abuse

Synthesis and Pharmacology of Potential Site-Directed Therapeutic Agents for Cocaine Abuse Susanna Moore 235 Pages Directed by Dr. David M. Collard and Dr. Howard M. Deutsch Stimulants such as cocaine continue to dominate the nations illicit drug problem. An effective medication for any aspect of cocaine addiction has not been developed. Cocaine binds, although not selectively, to the dopamine transporter (DAT) and disrupts normal dopamine (DA) neurotransmission between neurons. While the dopamine hypothesis for the mechanism of action of cocaine has been widely accepted, cocaine also possesses the ability to block the uptake of serotonin at the serotonin transporter (5-HTT) and norepinephrine at the norepinephrine transporter (NET). The purpose of the work described herein is directed towards synthesizing and testing compounds selective for the DAT, leading to the identification of candidates as potential pharmacotherapies for cocaine dependence. A series of disubstituted and trisubstituted [2.2.2] and [2.2.1]bicycles were synthesized and tested for inhibitor potency in [3H]WIN 35,428 (WIN) binding at the DAT and for inhibition of [3H]DA uptake. Based on results from some of the pharmacology data new regio- and stereochemical isomers of bicyclic [2.2.1]heptanes and [2.2.2]octanes were synthesized. This will lead to further structure-activity-relationships, which will provide a better understanding of the structural requirements needed to bind at the DAT.Ph.D