Immediate therapies are needed for the treatment of cocaine abuse worldwide. At present, there are no effective medications available to treat cocaine addiction. In order to develop agents that might find use in the treatment of cocaine abuse, the search for both cocaine antagonists and partial agonists is being pursued. While antagonists are more likely to find use in situations of cocaine overdose, the substitute agonist approach may prove more useful in maintenance programs. Compounds that possess the ability to mimic partially the effects of cocaine may help to maintain individuals in treatment programs while slowly withdrawing them from cocaine. Basically, what may be needed for cocaine abuse treatment is the pharmacological equivalent of a methadone, a drug widely used in the treatment of opiate abuse? In continuation of our past efforts to explore the structure-activity relationships of tropane analogs, we will continue to screen new compounds for their possible antagonist action. Additionally, in pursuit of a methadone type of approach, we intend to identify one or more tropanes that exhibit partial cocaine-like properties in vivo, and, specifically, substances that may elicit some of the same effects in the user as cocaine itself, but without causing the same degree of euphoria. As it is difficult to precisely define the pharmacological characteristics of transporter targeted ligands that may ultimately prove useful as cocaine medications, we believe it is essential to examine behaviorally a range of ligands showing varying degrees of DAT, NET, and 5-HTT activity, with the aim to identify the selectivity profile(s) that may be optimal for cocaine medication development. To date we have constructed a rich array of ligands that encompass elements of both structural diversity as well as varying levels of transporter inhibitory activity. 7 (1) For some of the classes of ligands already synthesized, further refine their transporter selectivity profiles through additional SAR studies; construct several new ligand classes including dimeric structures and GABA-mimetic/transporter conjugates; (2) Characterize pharmacologically all compounds by studying their ability to inhibit WIN35,428 binding, DA, NE, and 5-HT uptake using rat synaptosomal preparations; (3) Scale up selected compounds for animal behavioral studies to -be conducted by the Medications Development Division of NIDA; the compounds to be scaled up will be selected based upon their transporter affinities and selectivies.
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