title: C-ring cannabinoid lactones: a novel cannabinergic chemotype.
abstract: As a part of our controlled-deactivation ligand development project, we recently disclosed a series of (-)-Δ(8)-tetrahydrocannabinols (THCs) with a metabolically labile ester group at the 2'-position of the side chain. Now, we have replaced the C-ring in the classical THC structure with a hydrolyzable seven-membered lactone. One of the synthesized analogues binds with high affinity to the CB1 receptor (K i = 4.6 nM) and exhibits much lower affinities for the mCB2 and the hCB2. Also, in vitro functional characterization found the compound to be an agonist at rCB1. Consistent with our rational design, the lead cannabinergic lactone identified here is susceptible to metabolic inactivation by plasma esterases, while the respective acid metabolite is inactive at CB receptors. These results are highlighted with molecular modeling of the two regiosomeric lactones.
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.affiliation: Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Spyros P
authors.initials: SP
authors.lastname: Nikas
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: Jason Jianxin
authors.initials: JJ
authors.lastname: Guo
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: Srikrishnan
authors.initials: S
authors.lastname: Mallipeddi
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: JodiAnne T
authors.initials: JT
authors.lastname: Wood
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: Alexandros
authors.initials: A
authors.lastname: Makriyannis
keywords: Baeyer−Villiger rearrangement; Cannabinoids; lactones