title: Controlled-deactivation cannabinergic ligands.
abstract: We report an approach for obtaining novel cannabinoid analogues with controllable deactivation and improved druggability. Our design involves the incorporation of a metabolically labile ester group at the 2'-position on a series of (-)-Δ(8)-THC analogues. We have sought to introduce benzylic substituents α to the ester group which affect the half-lives of deactivation through enzymatic activity while enhancing the affinities and efficacies of individual ligands for the CB1 and CB2 receptors. The 1'-(S)-methyl, 1'-gem-dimethyl, and 1'-cyclobutyl analogues exhibit remarkably high affinities for both CB receptors. The novel ligands are susceptible to enzymatic hydrolysis by plasma esterases in a controllable manner, while their metabolites are inactive at the CB receptors. In further in vitro and in vivo experiments key analogues were shown to be potent CB1 receptor agonists and to exhibit CB1-mediated hypothermic and analgesic effects.
authors.affiliation: Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Rishi
authors.initials: R
authors.lastname: Sharma
authors.forename: Spyros P
authors.initials: SP
authors.lastname: Nikas
authors.forename: Carol A
authors.initials: CA
authors.lastname: Paronis
authors.forename: Jodianne T
authors.initials: JT
authors.lastname: Wood
authors.forename: Aneetha
authors.initials: A
authors.lastname: Halikhedkar
authors.forename: Jason Jianxin
authors.initials: JJ
authors.lastname: Guo
authors.forename: Ganesh A
authors.initials: GA
authors.lastname: Thakur
authors.forename: Shashank
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Othman
authors.initials: O
authors.lastname: Benchama
authors.forename: Jimit Girish
authors.initials: JG
authors.lastname: Raghav
authors.forename: Roger S
authors.initials: RS
authors.lastname: Gifford
authors.forename: Torbjörn U C
authors.initials: TU
authors.lastname: Järbe
authors.forename: Jack
authors.initials: J
authors.lastname: Bergman
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D000818:Animals; D002186:Cannabinoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002186:Cannabinoids; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2