Delta 9-Tetrahydrocannabinol (Delta9-THC), the primary CNS-active component of Cannabis sativa, is commonly known as a drug of abuse, but also has therapeutic potential. A series of non-classical cannabinoid analgetics (e.g. desacetyllevonantradol and CP-55,940) was developed at Pfizer Central research based on the structure of the 11-hydroxylated active metabolite of delta9-THC. My laboratory has utilized these potent cannabinoid analgetics as tools to elucidate the cellular mechanism of action of the CNS-active cannabinoid drugs. These compounds interact with a plasma membrane cannabinoid receptor in brain and neuronal cells to regulate production of the intracellular second messenger cyclic AMP. This project will continue studies to describe cellular and molecular mechanism(s) of action of the cannibimimetic compounds.
The Specific Aims are: 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 reconstitution with signal transducing G-proteins and development of antibodies to be further used to characterize the cannabinoid receptor. By understanding the biochemical properties of the cannabinoid receptor, we will be able to predict the actions of cannabinoid drugs in the brain. Tolerance and physical dependence may be based on cellular regulation of receptors. Dissociation of the untoward effects of cannabinoid drugs from the therapeutic effects will depend upon our understanding of the cannabinoid receptor interaction with signal transduction systems in the cell.
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