Novel Machaeriol Analogues as Modulators of Cannabinoid Receptors: Structure–Activity Relationships of (+)-Hexahydrocannabinoids and Their Isoform Selectivities

[Image: see text] Machaeriols are an important class of compounds that structurally resemble tetrahydrocannabinol (Δ(9)-THC), with the major differences being inverted stereochemistry at the ring junction as [6aR, 10aR] and an additional stereocenter at the C9 position of the A-ring due to saturation. A previous study reported that machaeriols did not show any cannabinoid receptor activity, even though these hexahydrodibenzopyran analogues mimic a privileged (+)-tetrahydrocannabinoid scaffold. To unravel structural requisites for modulation of cannabinoid receptors, a simple late-stage divergent approach was undertaken to functionalize the machaeriol scaffold using the Suzuki coupling reaction. Fourteen hexahydro analogues were synthesized and screened against both cannabinoid receptor isoforms, CB(1) and CB(2). Interestingly, many of the analogues showed a significant binding affinity for both receptors; however, two analogues, 11H and 11J, were identified as possessing CB(2) receptor-selective functional activity in the GTPγS assay; they were found to be micromolar-range agonists, with EC(50) values of 5.7 and 16 μM, respectively. Furthermore, molecular dynamics simulations between the CB(2) receptor and two novel analogues resulted in unique interaction profiles by tightly occupying the active ligand-binding domain of the CB(2) receptor and maintaining stable interactions with the critical residues Phe94, Phe281, and Ser285. For the first time, with the aid of structure–activity relationships of (+)-hexahydrocannabinoids, CB(2) selective agonists were identified with late-stage diversification using palladium-mediated C–C bond formation. By simply switching to (R)-citronellal as a chiral precursor, enantiomerically pure (−)-hexahydrocannabinoids with better CB(1)/CB(2) receptor isoform selectivity can be obtained using the current synthetic approach.