ANANDAMIDE--STRUCTURE ACTIVITY RELATIONSHIPS

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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 ad 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, the endogenous ligand which binds to this receptor was identified as arachidonylethanolamide, given the name anandamide (AN). Not much is known about this ligand but it belongs to a class of compounds called eicosanoids. These have no obvious chemical/structure-Activity Relationships (SAR) in the anandamide series. We feel this will be critical for understanding how AN and cannabinoids interact with the same recognition site. Our specific aims are (1) to develop SAR in AN series by systematically changing the ethanolamine part e.g. by changing the chain length between nitrogen and OH groups, changing the OH to nonhydrogen bonding groups, nitrogen, sulfur etc.; (2) to develop SAR by changing the arachidonic acid part e.g. by changing the number of double bonds in the chain including total saturation, changing the chain length, branching and substituting the chain at the end by -OCH(CH3)CH2CH2CH2Ph and -OCH(CH3)C5H11. These side chains are known to impart potent cannabinoid activity; (3) to study the effect of substitution by various alkyl groups on nitrogen and in the alpha position of the carbonyl in AN. These substituents will sterically affect the metabolic breakdown of the amide bond in AN. In addition we have proposed the synthesis of analogs in which the amide bond is replaced by an oxymethylene group in AN. The synthesis of these analogs and their subsequent biological evaluation will provide is 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.