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. The emphasis of this proposal is on further refining the new approach to tropanes so that novel analogs can be prepared that will have potent but selective binding to either the dopamine or 5-HT transporters. Cocaine analogs will be prepared with novel structural modifications including those which are conformationally constrained. A potential method for the treatment of cocaine addiction will also be examined using analogs that may alleviate craving by having a longer duration of action than cocaine. Highly hydrophobic cocaine analogs will be prepared as potential prodrugs that will be slowly metabolized to the active derivatives. The overall goals of this project are to generate novel probes to study the neurochemistry of cocaine addiction and ultimately, to lead to medications for the treatment of cocaine addiction.
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