A selective relevant 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 cocaine analogs in vivo and their binding affinity for the cocaine site in vitro. Characterization of this receptor may lead to information on the mechanism of action of cocaine. Studies of this nature require the availability of high affinity probes which can be used to label, visualize and solubilize the relevant binding protein. In Phase I, a tritium-labeled p-fluorophenyl cocaine analog was prepared whose higher affinity and specific activity represented a ten-fold improvement over tritiated cocaine. This new ligand was evaluated at cocaine binding sites in vitro and in drug discrimination experiments in vivo. In Phase II, additional derivatives of the fluorophenyl analog will be synthesized which will function as photoaffinity, covalent binding, PET, SPECT and fluorescent tagged probes. New cocaine analogs with varied substituents at the C-3 position will also be prepared. Extensive biological evaluation of these novel compounds will be performed in vitro and in vivo. It is anticipated that selective, high affinity ligands arising from this project will be commercially valuable products for pharmacological research centered on cocaine abuse.
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