A selective binding site for cocaine has been identified in brain membrane preparations from rodents, monkeys and humans. There is a high degree of correspondence between the relative potencies of various cocaine analogs in vivo and their binding affinity for the cocaine site in vitro. Information on the mechanism of action of cocaine may be gained by characterization of this receptor. Studies of this nature are dependent on the availability of a radiolabeled ligand with higher affinity and/or specific activity than tritiated cocaine. In Phase I, three novel cocaine analogs will be prepared in which the C-3 benzoyl group of cocaine is replaced by a p-fluorophenyl group, a modification which has been demonstrated to increase the potency of cocaine derivatives in behavioral studies above that of cocaine itself. The binding parameters of the analogs at the cocaine receptor in monkey brain will be measured. The most promising compound will be evaluated for cocaine-like activity in vivo by conducting behavioral studies in squirrel monkeys. This analog will be tritiated and its binding properties compared with those of tritiated cocaine. It is anticipated that a high affinity radioligand arising from this research will be a commercially valuable product for pharmacological research and drug screening applications. Phase II will involve chemical studies directed toward more potent analogs as well as more extensive biochemical and behavioral characterization in preparation for commercialization of products.
