Delta-9-Tetrahydrocannabinol(delta-9 THC)is the primary CNS-active component of Cannabis sativa. Cannabinoid analgetics, including desacetyllevonantradol and CP-55940, potently mimic the effects of delta-9 THC in a number of animal models. Using these potent cannabinoid compounds, my laboratory determined that the cellular mechanism of action of the CNS-active cannabinoid drugs was to inhibit adenylate cyclase via G-i. We radiolabeled CP-55940 and developed a receptor binding assay to biochemically characterize the cannabinoid receptor. This work will continue with the following goals: 1. Characterization of the cellular regulation of the cannabinoid receptor in neuronal cells including synthesis, post-translational processing, transit to the plasma membrane, and potential sequestration in response to chronic agonist stimulation; 2. Characterization of the structural properties of the cannabinoid receptor and determination of the functional concomitants; 3. Purification of the cannabinoid receptor and use of the purified protein for structure analysis, antibody production, reconstitution with signal transducing G-proteins and to purify an endogenous cannabinoid-like binding activity for the cannabinoid receptor. 4. Identification of an endogenous cannabinoid-like binding activity present in the CNS, and purification ana characterization of the factor(s) responsible for this action at the cannabinoid receptor. Production of antibodies for the endogenous cannabinoid-like binding factor(s) and development of immunoassays.
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