Cocaine addiction persists as a problem of national significance. The goals of this project are to develop a fundamental understanding of the targets of cocaine in the brain at the molecular level and use this information to investigate the therapeutic potential of drugs that bind to these targets. Accumulating evidence suggests that the dopamine transporter is a principal mediator of cocaine in the brain. Current models propose that the binding of cocaine and dopamine to the transporter requires the formation of an ionic bond between a basic amine nitrogen of the ligand and a counterion (aspartic acid) on the transporter. To explore this premise, we developed non-amine ( nonamines ) nitrogen bearing cocaine analogs (aryloxatropanes). These nonamines bind with high affinity to monamine transporters and block dopamine transport in COS-7 cell and engender cocaine-like subjective effects in monkeys. The findings invalidate the premise that transporter drugs require an amine nitrogen. We will determine the structure-activity relationships of nonamines at monoamine transporters in brain. High affinity nonamines will be tested in cell lines expressing wild-type and in mutant forms of the transporter in which the aspartic acid counterion is exchanged for other amino acids. The most promising compound(s) will be radiolabled for further investigation of the binding domains on monoamine transporters. These unique nonamines will increase our understanding of drug-transporter interactions and open avenues for discovery of a new generation of drugs targeted to monamine transporters. To explore the potential of nonamines and their nitrogen-bearing counterparts as cocaine replacement therapy, we will investigate their ability to mimic the subjective effects of cocaine, determine whether they maintain i.v. self-administration, which is predictive of compound's abuse liability, and determine the degree to which they modify the self-administration of cocaine, which is predictive of their therapeutic utility as a cocaine replacement. Our multidisciplinary approach to cocaine research will provide fundamental information on the neurobiology of cocaine with direct relevance to cocaine medications.
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