The drug abuse problem in general and the wide spread use of marijuana in particular has focused attention on the chemistry and pharmacology of this plant (Cannabis Sativa). Although rapid advances have been made in the chemistry and pharmacology of this class of compounds, the mechanisms involved in producing the various central nervous effects (CNS) have not been established. The long term goal of our synthetic program is to develop delta 9- tetrahydrocannabinol (THC) analogs which will prove to be useful tools in elucidating the mechanism of action of cannabinoids.
Our specific aims are to synthesize (i) a series of delta 9,11-THCs with varied aromatic side-chains as potential antagonists based on a lead that in the monkey test, pretreatment with delta 9,11-THC attenuated the delta 9-THC induced ptosis, sedation, ataxia and operant behavior; (ii) delta 8-THC analogs with the N-bis(2- chloroethyl) functional group present at C-11, 12 beta-, 3'- and 5'-positions as potential receptor probes and antagonists; (iii) three pairs of C-2', 3'- and 4'-hydroxy- delta 9-THC in their R and S forms; and (iv) a series of amide derivatives of 9-nor-9-carboxy- delta 8-THC as potential antagonists. The synthesis of these analogs and their subsequent biological evaluation could provide us with new knowledge about Structure Activity Relationships (SAR) in cannabinoids; it could lead to the discovery of an antagonist which would help in the identification of cannabinoid receptors and thus result in a rapid advance in this field. The discovery of an antagonist will also prove to be a valuable tool in assessing the dependence producing properties of delta 9-THC. The proposed study will give a deeper understanding, at least in part, of the mechanisms involved in the pharmacological action of these compounds and will help to combat the drug abuse problem which has had profound effects on our present day society.
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