The proposed study will seek to identify the molecular features involved in cannabimimetic activity through the design, synthesis and biological testing of novel compounds. It is motivated by the recent discovery of a cannabinoid receptor in mammals and man. Our design recognizes four molecular fragments contributing to cannabimimetic activity; (a) a phenolic hydroxyl, (b) a side chain attached to the phenolic ring, (c,d) two aliphatic hydroxyl groups in the northern and southern ends of the molecule. The proposal focuses on the side chain (SC) and the southern aliphatic hydroxyl (SAH) fragments whose stereochemical requirements are not well characterized. We shall study the stereoelectronic properties of the novel cannabinoids; (a) in solution and in the membrane using modern high resolution NMR techniques, (b) theoretically using molecular mechanics and ab initio calculations. The data from the above methodologies will then be integrated to give detailed information on the molecular properties of each of the cannabinoids. Analogs will be tested (a) on a variety of behavioral test systems and for analgesic activity in mice, (b) for THC discrimination in rats. Both agonistic and antagonistic activities will be considered. Special attention will also be given to identifying analogs which demonstrate a separation between analgesic and psychotropic properties. Analogs will also be tested for their affinities for the cannabinoid receptor sites in the brain. Our studies will seek to correlate the molecular properties of the novel cannabinoids with their pharmacological and biochemical (affinities for receptor) properties. These correlations should provide valuable information on specific structural requirements for cannabimimetic activity. The studies should also help us identify subtypes of cannabinoid receptors if such subtypes exist. The therapeutic targets of the proposal include the development of (a) non-opioid analgesics which are also devoid of the known psychotropic properties of cannabinoids, and the addictive properties of opioids (b) specific antagonists which can antagonize the ill effects of cannabinoids. Hopefully, this project will either result in the development of new therapeutic analogs or will provide useful information for the design of such drug molecules.
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