C‑Ring Cannabinoid Lactones: A Novel Cannabinergic Chemotype

As a part of our controlled-deactivation ligand development project, we recently disclosed a series of (−)-Δ⁸-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.