In order to carry out a detailed study of the cocaine receptor, we have synthesized and tested a large number of cocaine analogs in collaboration with Dr. Ivy Carroll at RTI. For example, we found that analogs of cocaine that are also analogs of WIN 35,428 are potent in ligand binding studies as well as in dopamine transport studies in rat striatal tissue. These analogs are the most potent cocaine analogs known, some of them being 80 to 100 times more potent than cocaine itself. We have also synthesized 3H-WIN 35,065-2 and carried out binding studies because it is a potent cocaine compound that has been studied by a variety of laboratories. These compounds also contribute substantially to structure-activity relationship information. We have shown that halogen substituents on the phenyl ring at the C3 carbon can increase potency. These studies have implications for understanding the nature of the cocaine receptor in the binding region of the molecule. We have also utilized irreversible binding ligands at the cocaine receptor/dopamine transporter to study the carbohydrate moiety of the protein molecule. Our results indicate that the carbyhydrate is rich in sialic acid residues and is probably N-linked to the protein.
