SYNTHESIS OF SR141716A AND ANANDAMIDE ANALOGS

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The drug abuse problem in general and the widespread use of marijuana in particular have focused attention on the chemistry and pharmacology of the plant Cannabis Sativa. Although rapid advances have been made in the chemistry and pharmacology of this class of compound called cannabinoids, the mechanisms involved in producing the various central nervous effects have not been established. A few years ago, it was shown that cannabinoids act by binding to a G-protein-coupled receptor in the brain and very recently, a family of endogenous ligands named anandamides (AN) belonging to a class of compounds called eicosanoids, has been identified. In addition, an antagonist SR141716A, a pyrazole derivative has been discovered. These have no obvious chemical/structural relationship with cannabinoids. The goal of the proposed synthetic research is to generate chemical probes which will help in understanding how such diverse structures as THC's (delta9-THC), eicosanoids (AN), aminoalkylindoles (AAI) and the antagonist SR141716A interact with the same recognition site. Our Specific Aims are to synthesize (1) A analogs of very high potency which could act as pharmacological/biochemical probes. (2) SR141716A analogs which will identify the lipophilic site in SR141716A and thus provide critical information in molecular modeling for alignment studies with the cannabinoid pharmacophore (3) endogenous ligands and the antagonist SR141716A in large quantities (several grams) and make them available for further biological studies. The synthesis of these analogs and their subsequent biological evaluation will highlight the differences which may exist between the various types of canabimimetics. In addition they will provide cannabinoid probes for both in vitro and in vivo studies and the data could point us in the direction of cannabinoid receptor subtypes. The proposed study will therefore help our understanding of the pharmacological action of this important class of compounds.