The drug abuse problem in general and the wide spread use of marijuana in particular has focused attention on the chemistry and pharmacology of cannabinoids. 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 the synthetic program is to develop delta-9-tetrahvdrocannabinol (THC) analogs which will prove to be useful tools in elucidating the mechanism of action of cannabinoids. The present emphasis will be directed toward: (a) developing cannabinoid analogs with a specific pharmacological profile as analgesics (b) examining the profile of the 'silent antagonist' (c) developing and designing CB2 selective ligands (d) studying the role of the C-I substituent in THCs in 'ligand-receptor' interactions and (e) delineating between peripheral and central effects of cannabinoids. All these goals represent a continuation of the current program which has generated several noteworthy leads.
The specific aims are (1) development of agonists with selective pharmacological profiles, (2) development of 'silent antagonists', (3) development of CB2 selective THCs, (4) examine the nature of C-I substituent interactions with the receptor, (5) study peripheral acting agonists and antagonists and (6) generate new biological leads.The knowledge gained from the synthesis and pharmacological study of these analogs could be vital in the study of Structure Activity Relationships(SAR), tolerance, dependence and in the development of therapeutically useful drugs, and will lead to a better understanding of the mechanism of action of cannabinoids and will help combat the problem of drug abuse.
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