ANANDAMIDE CONFORMERS TO PROBE THE CANNABINOID RECEPTOR

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DESCRIPTION: (Applicant's Abstract) The systematic study of analogs of the endogenous cannabimimetic, anandamide, has the long term, health related potential to further knowledge of the biochemical mechanism of action of this neurotransmitter and the new neurochemical system it represents. Mapping of ligand interaction sites and the identification of receptor subtypes are additional objectives. Also, analogs could be generated with dissociated pharmacological effects resulting in more specific drugs and biochemical probes with psycho dynamic activities of interest. These have potential application to studies of drug abuse, brain function, and immuno-modulation. The specific aims of the proposed work is the design, synthesis, pharmacological testing, and molecular modeling of conformationally restricted anandamide analogs to probe a sector of conformational space that chemical and computational data suggest as the active conformation of anandamide. It is theorized that the active conformation of anandamides is a bent or "J" like structure which exhibits remarkable overlap with active cannabinoids as regards both shape and electrostatic potentials at its receptor accessible surface. Locking such conformations is expected to enhance activities and potentially dissociate biological effects in this class of compounds. Compounds designed to test the theory are ring constrained structures, based on preliminary molecular dynamics studies of anandamide and reported chemistry of other arachidonic acid derivatives, that examines the hypothesized sector of conformational space with small, medium and macrocyclic ring analogs. The compounds explore the effects of the position of the bend in the acyclic 20-carbon chain of anandamide, the configurational differences at chiral centers, and the degree of conformational freedom as influenced by various ring systems. It is further theorized that interaction between the pi electrons of the ligand and cationic sites in the receptor play a key role in binding. This is tested in analogs with both enhanced and reduced pi character in a way that separates the conformational and the electrostatic effects of the carbon-carbon double bonds. Putative metabolites of anandamide and the analogs are examined as they are potential active forms of this class of ligands. The research program is designed to test and evolve an SAR theory and discover active analogs by computationally guided synthesis, in vitro and in vivo testing, and computational analysis to refine subsequent cycles of design, synthesis and testing. Testing will involve accepted receptor binding assays, inhibition of mouse isolated vas deferens twitch response, and in vivo testing in the mouse to identify active compounds.