Cannabinoid receptors 1 (CB1) and 2 (CB2) are key components of the endocannabinoid system and play central roles in regulating diverse physiological processes, including neural signaling, immune modulation, and inflammation. Both receptors belong to the Class A G protein-coupled receptor (GPCR) family and exhibit distinct tissue distributions and signaling profiles, making them attractive yet challenging targets for receptor-specific drug development. Efforts to design subtype-selective ligands have been hindered by the high degree of sequence and structural similarity between CB1 and CB2, resulting in widespread ligand cross-reactivity. Recent advances in structural biology have yielded high-resolution structures of both CB1 and CB2 in multiple functional states, providing new opportunities to dissect the molecular determinants of receptor selectivity. In this review, we present a comprehensive comparative analysis of CB1 and CB2 structures, with a focus on differences in ligand-binding residues, binding pocket topology, and physicochemical environments that may influence subtype selectivity and signaling. Our analysis suggests that CB1 preferentially accommodates bulkier and more flexible ligands, whereas CB2 favors smaller and more compact chemotypes. In addition, positionally conserved but chemically distinct residues (e.g., Leu193 in CB1 vs. Ile110 in CB2 and Leu359 in CB1 vs. Val261 in CB2) highlight subtle structural differences that can influence ligand binding and receptor activation. Overall, this work aims to inform the rational design of next-generation cannabinoid ligands with enhanced receptor selectivity, reduced side effects, and improved therapeutic potential.
Varghese et al. (Thu,) studied this question.