Although the cannabinoid receptor in the brain was identified several years ago, and its primary structure was determined, little is known concerning the detailed geometry. A three point receptor model has been suggested to explain the classical structure activity relationships for cannabinoids, however a number of classes of non-traditional indole- and pyrrole-based cannabinoids have been prepared recently. In addition, a cannabinoid antagonist which is a pyrazole derivative has been synthesized, and an endogenous cannabinoid, which is an amide of arachidonic acid has been isolated from porcine brain. The long-term objectives of this research are to obtain definitive information concerning the geometry of the lipophilic portion of the receptor which interacts with the alkyl side chain present in all active traditional cannabinoids, and to correlate the structural features of the cannabimimetic indoles and pyrroles with those of more traditional cannabinoids. An additional goal is to develop criteria for antagonist activity in the cannabinoid field. These objectives will be reached through a collaborative effort with Dr. Billy R. Martin of the Medical College of Virginia.
The specific aims of the proposed research include the synthesis and examination of the pharmacology of a series of cannabinoids in which the natural n-pentyl side chain is replaced by either a 1,2-dimethylheptyl or a methylheptyl group. The stereochemistry of the alkyl substituents will be controlled in order to gain insight into the detailed geometry of the receptor. This work is an extension of current studies in which a single methyl group is appended to the n-pentyl side chain of delta8- tetrahydrocannabinol. Also, two compounds in which the side chain is constrained in a ring will be prepared. A number of additional indole derivatives will be prepared, the structures of which have been designed on the basis of those of cannabimimetic indoles synthesized in this laboratory. In order to investigate the structural criteria for antagonist activity, several indoles and pyrroles which contain some of the structural features of the known pyrazole antagonist will be synthesized, and their pharmacology evaluated. In addition to the compounds designed to gain insight into receptor geometry, hydroxylated metabolites of CP 55,940 and 11-hydroxy-3-(1',1'- dimethylheptyl)-delta8-THC will be synthesized both as reference compounds and for pharmacological evaluation. To complete the current studies of the effect of stereochemistry at C-9 of the cannabinoid molecule on biological activity, several delta10-THC derivatives will be synthesized.
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