Bridging the Binding Sites 2.0: Photoswitchable Dualsteric Ligands for the Cannabinoid 2 Receptor.

The cannabinoid receptor 2 (CB ₂ R) has high, unexploited therapeutic potential in several central nervous system disorders due to its involvement in neuroinflammatory processes and pathologies like neurodegeneration. Dualsteric/bitopic ligands are currently developed to achieve receptor subtype selectivity and biased signaling. To obtain a molecular tool compound with photoswitchable potential dualsteric properties, we applied two different approaches to link a positive allosteric modulator with an orthosteric agonist via a photochromic unit. We characterized the photophysical properties of all compounds and determined efficacy in internalization, calcium mobilization, and BRET studies. We report the first potentially dualsteric photoswitchable ligand for studying molecular mechanisms of CB ₂ R-associated pathologies. Compound 17 - para is a submicromolar " cis -on" agonist with >10-fold higher potency compared to its trans photoisomer and allows high spatiotemporal control of CB ₂ R activation.