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 delta9-tetrahydrocannabinol (THC) analogs which will prove to be useful tools in elucidating the mechanism of action of cannabinoids. The present emphasis will be directed toward: (1) designing new analogs which will clarify the cannabinoid pharmacophore and (2) designing analogs which are antagonists. In addition the goal of developing cannabinoid analogs with a limited pharmacological profile represents a continuation from the current grant. The new analogs will be modelled after THCs and structural hybrids containing features of both THCs and aminoalkylindoles.
Our specific aims are to synthesize (1) novel aminoalkylindoles carrying at position 4 of the indole, side chains which are optimum for activity in THCs; (2) delta8/delta9-THCs with side chain containing double or triple bonds, and phenyl group with trifluoromethyl substituent at various positions; (3) the corresponding amino and alkylamino compounds in both the R and S series as an extension of the ongoing work on 2',3',4'-side chain hydroxylated delta9-THCs' (4) delta8-THC analogs with the N-bis(2- chloroethyl) functional group present at 3'- and 5'-positions as potential receptor probes and antagonists; (5) novel ester and amide derivatives of 9-nor-9-carboxy-delta9-THC in both the (-)- and the (+)- series. 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 search for an endogenous ligand for cannabinoid activity 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 delta9-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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