Structural basis of Δ⁹-THC analog activity at the Cannabinoid 1 receptor

Δ⁹-tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. THC's psychoactive actions are mediated primarily by the cannabinoid receptor CB₁. Here, we determine the cryo-EM structure of HU210, a THC analog and widely used tool compound, bound to CB₁ and its primary transducer, G_i1. We leverage this structure for docking and 1,000 ns molecular dynamics simulations of THC and 10 structural analogs delineating their spatiotemporal interactions at the molecular level. Furthermore, we pharmacologically profile their recruitment of G_i and β-arrestins and reversibility of binding from an active complex. By combining detailed CB₁ structural information with molecular models and signaling data we uncover the differential spatiotemporal interactions these ligands make to receptors governing potency, efficacy, bias and kinetics. This may help explain the actions of abused substances, advance fundamental receptor activation studies and design better medicines.