Stimulants, such as cocaine, continue to dominate the nation's illicit drug problem. An effective medication for any aspect of cocaine addiction does not exist. The purpose of the work described here is directed towards combining medicinal chemistry and preclinical pharmacology to design, synthesize, and test site-directed compounds leading to the identification of candidates as potential pharmacotherapies for cocaine dependence. A series of bicyclo[2.2.2] and [2.2.1] alkane derivatives will be synthesized which combine the potency and selectivity of the GBR class of compounds in a framework similar to the tropane core of cocaine. Modification of the rigid framework (stereochemistry, substituents on the framework and phenyl ring, type of amine, etc.) will be accomplished by several routes. These reaction schemes allow for the rapid generation of a plethora of target molecules to explore binding to the DAT and establish structure-activity relationships (SARs). All of the molecules synthesized will be tested in vitro for their ability to inhibit the binding of [3H] WIN 35,428 to rat striatal membrane preparations and the uptake of [3H]dopamine (DA) into rat striatal sybnaptosomes. In vitro inhibition of [3H]5-hydroxtryptamine (5-HT, seratonin) and [3H]norepinephrine (NE) will also be measured to establish relative selectivity of the congeners for the various transporters. Results of the SARs will aid in the development of new therapeutic agents for cocaine addiction.
