This application is for the continuation of support of a collaborative program with Dr. Michael Kuhar of the Addiction Research Center (ARC) to study the biochemical mechanism of cocaine addiction. The potency of cocaine and cocaine-like drugs in self-administration studies correlates with their potencies in inhibiting radioligand binding to the dopamine uptake site. Since there is no correlation for binding to a large number of other pre- and post-synaptic binding sites the cocaine receptor related to substance abuse appears to be the one associated with dopamine uptake inhibition. We propose to: (1) conduct a structure-activity study oh cocaine analogs; (2) develop new cocaine analogs which will bind specifically and irreversibly to the receptor; (3) develop new cocaine derivatives that will be suitable for purification of the receptor by affinity chromatography; and (4) develop new cocaine analogs for use in Single Photon Emission Tomography (SPECT). Information gained from these studies will lead to a better understanding of the basic biochemical mechanism(s) of cocaine addiction. Our program has been expanded to include collaboration with Dr. Robert Balster of the Medical College of Virginia who will conduct drug discrimination studies in rats land drug self-administration studies in rhesus monkeys on selected compounds. We hope that these collaborative programs which combine design of analogs by molecular modeling, chemical synthesis, receptor binding, and functional studies will identify analogs that will share some but not all of the actions of cocaine and thus may lead to therapeutically useful drugs.
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