Origin of the Different Binding Affinities of (9<i>R</i>)- and (9<i>S</i>)-Hexahydrocannabinol (HHC) for the CB₁ and CB₂ Cannabinoid Receptors

Hexahydrocannabinols (HHCs) are emerging cannabinoids that have become available for recreational use and were recently classified as Schedule II under an international treaty. Although often advertised for having desirable effects, recent studies have shown that commercial products typically contain variable amounts of two epimers, (9<i>R</i>)-HHC and (9<i>S</i>)-HHC. In turn, these epimers have been shown to have different binding affinities to the CB₁ and CB₂ receptors. We report a computational study that interrogates the origins of these differing affinities. Molecular docking and molecular dynamics simulations were employed to investigate the binding of (9<i>R</i>)-HHC and (9<i>S</i>)-HHC to cannabinoid receptors CB₁ and CB₂. Computational results show key binding interactions and highlight important conformational effects. For both receptors, the (9<i>R</i>)-HHC isomer exists primarily in a chair conformation, placing the C9 methyl substituent in a favorable equatorial position in the active sites. However, (9<i>S</i>)-HHC exists in equilibrium between the chair and twist-boat conformations within the receptor's active site, ultimately leading to less favorable binding in the CB₁ and CB₂ active sites, making (9<i>S</i>)-HHC a less favorable ligand compared to (9<i>R</i>)-HHC. These studies explain the relative binding of HHCs and are expected to enable the investigation of other cannabinoids that display improved or selective receptor binding.