A photoswitchable ligand for opposite control over cannabinoid receptors CB1 and CB2.

Photopharmacology offers a powerful strategy for the spatiotemporal modulation of protein function with molecular precision. While all the current photoswitchable ligands developed to date act on single targets, we report Azo23, the first bifunctional photoswitchable ligand that exerts opposing efficacy modulation toward two closely related G protein-coupled receptors, cannabinoid receptors CB1 and CB2. Upon ultraviolet irradiation, Azo23 isomerizes from its trans to cis form, resulting in a potent CB1 agonist and CB2 antagonist, with a remarkable activity shift exceeding 50-fold. Molecular dockings reveal distinct receptor interactions underlying this dual behavior. Azo23 thus represents a unique photopharmacological tool for dissecting the complex and often overlapping roles of CB1 and CB2, and emerges as a promising lead compound for light-controlled modulation of cannabinoid signaling.