COMPARATIVE RECEPTOR-BINDING ANALYSES OF CANNABINOID AGONISTS AND ANTAGONISTS

To further characterize neuronal cannabinoid receptors, we compared th e ability of known and novel cannabinoid analogs to compete for recept or sites labeled with either [H-3]SR141716A or [H-3]CP-55,940. These e fforts were also directed toward extending the structure-activity rela tionships for cannabinoid agonists and antagonists. A series of altern atively halogenated analogs of SR141716A were synthesized and tested i n rat brain membrane binding assays along with the classical cannabino ids, Delta(9)-tetrahydrocannabinol, cannabinol, cannabidiol, the noncl assical cannabinoid CP-55,940, the aminoalkylindole WIN55212-2 and the endogenous fatty acid ethanolamide, anandamide. Saturation binding is otherms were performed with both radioligands, as were displacement st udies, allowing an accurate comparison to be made between the binding of these various compounds. Competition studies demonstrated that all of the compounds were able to displace the binding of [H-3]CP-55,940 w ith rank order potencies that agreed with previous studies. However, t he rank order potencies of these compounds in competition studies with [H-3]SR141716A differed significantly from those determined with [H-3 ]CP-55,940. These results suggest that CP-55,940, WIN55212-2 and other agonists interact with cannabinoid binding sites within the brain whi ch are distinguishable from the population of binding sites for SR1417 16A, its analogs and cannabidiol. Structural modification of SR141716A significantly altered the affinity oi the compound and its relative a bility to displace either [H-3]CP-55,940 or [H-3]SR141716A preferentia lly within the rat brain receptor membrane preparation.