ANANDAMIDE--STRUCTURE/ACTIVITY RELATIONSHIPS

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DESCRIPTION (Applicant's Abstract): 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 saliva. 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 (CB1), and arachidonylethanolamide called anandamide (AN), was identified as the endogenous ligand. The long term goal of this program is to develop the Structure-Activity Relationships (SAR) of ANs which are eicosanoids, and bear no chemical/structural relationship with cannabinoids. We feel the SAR of ANs will be critical for understanding how AN and cannabinoids interact with the same receptor. The present emphasis will be directed toward developing (1) potent agonists and potential antagonists; (2) novel structural analogs; (3) hydroxy-AN analogs as potential metabolites and (4) selective amidase inhibitors. All these goals represent a continuation of the current program which has generated several noteworthy leads. The specific aims are to (1) continue to examine the SAR of arachidonic acid part of AN; (2) continue to examine the SAR of the ethanolamine part of AN; (3) synthesize hydroxylated AN analogs; (4) develop novel AN/THC analogs; (5) develop a selective and potent amidase inhibitor. The synthesis of these analogs and their subsequent biological evaluation will provide us with SAR in the AN series and will highlight the differences which may exist between this series and THCs and allow a better understanding of their interrelationship. The data could point us in the direction of cannabinoid receptor sub-types and even help in the discovery of an antagonist. In addition they will provide cannabinoid probes for both in vitro and in vivo studies. The proposed study will therefore help in our understanding of the pharmacological action of this important class of compounds.