title: Comparative receptor binding analyses of cannabinoid agonists and antagonists.
abstract: To further characterize neuronal cannabinoid receptors, we compared the ability of known and novel cannabinoid analogs to compete for receptor sites labeled with either [3H]SR141716A or [3H]CP-55,940. These efforts were also directed toward extending the structure-activity relationships for cannabinoid agonists and antagonists. A series of alternatively halogenated analogs of SR141716A were synthesized and tested in rat brain membrane binding assays along with the classical cannabinoids, Delta9-tetrahydrocannabinol, cannabinol, cannabidiol, the nonclassical cannabinoid CP-55,940, the aminoalkylindole WIN55212-2 and the endogenous fatty acid ethanolamide, anandamide. Saturation binding isotherms were performed with both radioligands, as were displacement studies, 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 [3H]CP-55,940 with rank order potencies that agreed with previous studies. However, the rank order potencies of these compounds in competition studies with [3H]SR141716A differed significantly from those determined with [3H]CP-55,940. These results suggest that CP-55,940, WIN55212-2 and other agonists interact with cannabinoid binding sites within the brain which are distinguishable from the population of binding sites for SR141716A, its analogs and cannabidiol. Structural modification of SR141716A significantly altered the affinity of the compound and its relative ability to displace either [3H]CP-55,940 or [3H]SR141716A preferentially within the rat brain receptor membrane preparation.
authors.affiliation: Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.
authors.forename: B F
authors.initials: BF
authors.lastname: Thomas
authors.forename: A F
authors.initials: AF
authors.lastname: Gilliam
authors.forename: D F
authors.initials: DF
authors.lastname: Burch
authors.forename: M J
authors.initials: MJ
authors.lastname: Roche
authors.forename: H H
authors.initials: HH
authors.lastname: Seltzman
mesh_terms: D000700:Analgesics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002186:Cannabinoids / Q000819:agonists* / Q000037:antagonists & inhibitors*; D003511:Cyclohexanols / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D010880:Piperidines / Q000378:metabolism* / Q000494:pharmacology; D011720:Pyrazoles / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D000077285:Rimonabant
chemical_list: D000700:Analgesics; D002186:Cannabinoids; D003511:Cyclohexanols; D010880:Piperidines; D011720:Pyrazoles; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077285:Rimonabant