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 led to a series of extremely potent cocaine analogs. In this proposal, the extension of the synthetic strategy will be used to prepare an array of elaborate heterobicyclic and tricyclic systems, that will be evaluated for their binding affinities at the monoamine transporters. The targets have been designed on the assumption that a combination of a nitrogen functionality (or related group), an aryl functionality and a second hydrophobic functionality is required for binding. By introducing these functionalities on various heterobicyclic or tricyclic scaffolds, their arrangement is subtly altered from how it was in the tropane derivatives. The overall goals of this project are to generate novel probes to study the neurochemistry of cocaine addiction and ultimately, to generate medications for the treatment of cocaine addiction. The proposed studies will ensure that a greater structural diversity is brought into the types of compounds that will be considered as potential medications for the treatment of cocaine addiction.
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