Due to the severe problems of cocaine abuse, a dramatic need has arisen to study related compounds in order to enhance the understanding of the biological processes involved and to develop medications for the treatment of cocaine addiction. The rigidity of the tropane skeleton offers an ideal framework for generating well-defined molecular probes to study the subtleties behind the neurobiology of cocaine action. This proposal will describe the synthesis of a series of novel cocaine analogs based on the tropane structure. A comparison of the affinities of these analogs with cocaine and mazindol in binding to putative dopamine uptake sites in striatal membranes, using the potent tropane analog [3H]CFT(WIN 35428) as a radiolabeled ligand will also be undertaken. The affinity data will give information on the structural requirements at C-2 for effective binding and determine the effect of functionality at C-5. The compounds were chosen because of the significance of the WIN compounds in cocaine drug abuse research. Flexibility for the generation of new derivatives of the WIN compounds is currently limited, however, because the available scheme starts from cocaine. The first enantioselective approach to cocaine analogs, which does not start with tropane natural products nor involves a resolution is planned. The synthetic design is based on vinylcarbenoid intermediates which the Principal Investigator has shown to be extremely useful for the synthesis of seven-membered rings. The reaction between vinylcarbenoids and pyrroles would be a very direct and general approach to tropane alkaloids. The proposed research involves basic synthetic organic chemistry directed towards the optimization of enantioselectivity in this scheme. Three sites are available for chiral auxiliaries, the pyrrole, the carbenoid and the catalyst, which ensures considerable flexibility to engineer efficient enantioselectivity.
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