Structural basis of THC analog activity at the Cannabinoid 1 receptor

THC analogs modulate the cannabinoid receptor CB1 through distinct ligand-receptor interactions that shape potency, efficacy, signaling bias, and kinetics. Using cryo-EM, the study determines the structure of the THC analog HU210 bound to CB1 and the primary transducer G(i1). The authors then use this structural template for docking and 1000 ns molecular dynamics simulations of THC and 10 structural analogs, mapping how specific ligands make spatiotemporal contacts with the receptor. They also pharmacologically profile how these compounds recruit G(i) and beta-arrestins and measure reversibility of binding from an active complex. By combining structural coverage with molecular models and signaling data, the work provides a mechanistic explanation for why THC-related compounds differ in pathway bias and dynamics, with implications for fundamental CB1 activation studies and design of improved cannabinoid medicines.