The purpose of this work is to synthesize and test compounds which will be useful therapeutic agents in the treatment of stimulant abuse. Synthetic efforts will center around the derivatization of two indirect acting dopamine agonists, methylphenidate and LR-5182 (a bicyclooctane).
The aim i s to alter their basic structures in such a manner as to generate either (1) potent, long-lasting agonists which will substitute for the abused (analagous to methadone in the treatment of heroin addiction), (2) partial agonists or mixed agonist-antagonists which will lessen the subjective effects of the abused stimulant, but exhibit a mild stimulant effect of their own; or (3) antagonists, which will block the subjective effect of the abused stimulant, but have no intrinsic stimulant activity. The compounds will be evaluated using a multi-tiered battery of tests. The first level will consist of the in vitro determination of potency to block dopamine uptake and [3H]WIN 35,428 binding, selectivity for the dopamine transporter, and right-shift of the cocaine inhibition curve against dopamine uptake Based on the outcome, some compounds will progress to the second level of testing, where their ability to substitute for and/or antagonize cocaine in drug discrimination and conditioned place preference tests in rats will be assessed. Compounds judged to have therapeutic potential at this point will then advance to testing in primate self-administration and drug- discrimination paradigms. Although the aim is to develop agents for the treatment of stimulant abuse, the findings may also have application in other disorders involving dopaminergic pathways, including attention deficit disorder, Parkinson's disease, Tourette's syndrome, and schizophrenia.
