Essential Dynamics of CB ₁ Receptor-Agonist Complexes: Implications for Signalling Bias

The CB ₁ cannabinoid receptor is implicated in a broad range of physiological processes and disease states, however CB ₁ -targeting drugs in clinical use remain based on tetrahydrocannabinol (THC). Ligands that exhibit functional selectivity for different intracellular signalling pathways are currently an area of rapid development, and hold significant potential as therapeutic agents. Improved understanding of the exact molecular mechanisms underpinning biased activation of intracellular effector proteins for CB ₁ is necessary to enable drug development of biased CB ₁ ligands into candidates for treatment of human disease. Using molecular dynamics, this study shows that CB ₁ conformations resulting from activation by the orthosteric ligands CP55940, Δ9-THC or 5F-MDMB-PICA exhibit differences in the dynamic organisation of key residues and receptor substructures involved in coupling to G proteins and β-arrestins, that leads to selective activation of downstream signalling pathways. The identification of conformationally distinct CB ₁ -agonist complexes that demonstrate different functional profiles provides an important step in unravelling the molecular determinants for biased signalling, and lays a platform for future rational design of novel therapeutic leads.