Due to the severe drug abuse problems of the tropane alkaloid, cocaine, a dramatic need has arisen to study related compounds which may enhance the understanding of the biological processes involved in cocaine addiction. In recent years a number of novel cocaine analogs, based on the tropane structure, have been found to be useful tools to study the mode of action of cocaine. The standard synthetic scheme to these compounds, however, begins with cocaine, and so, lacks flexibility. A novel synthetic strategy to tropanes based on the reaction between vinylcarbenoids and pyrroles has lead to a series of extremely potent cocaine analogs, and these and related compounds will be studied widely within the Center. The central mission of the Chemistry Core is to prepare a series of novel tropanes in sufficient quantities for extensive evaluation within the Center. Some of the tropanes are promising as potential medications for the treatment of cocaine addiction, while others are useful chemical probes that will be utilized to study underlying questions of drug abuse research. In particular, a series of compounds will be made available to determine if the therapeutic utility of a cocaine analog can be enhanced by modification of the binding affinity selectivity between the dopamine and serotonin. A second series of compounds will be prepared in order to evaluate the general hypothesis that a potential medication approach to cocaine addiction would be to develop long acting cocaine agonist. The Core will supply these novel compounds to virtually every component of the Center, and furthermore, will supply the NIDA Medication Development Program with compounds that have promising therapeutic potential. The other goals of the Core will be to design and prepare novel tropanes with specific biological properties. Novel pro-drugs to the active tropanes will be prepared. New irreversible ligands and photoaffinity agents for the dopamine and serotonin transporters will be prepared. Also, the synthetic method that is central to this work will be further refined in order to make it applicable to large scale synthesis.
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