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The cannabinoid receptor type 2 (CB 2 R) is a G protein-coupled receptor with therapeutic potential for the treatment of inflammatory disorders. Fluorescent probes are desirable to study its receptor localization, expression and occupancy. Previously, we have reported a photoaffinity probe LEI-121 that stabilized the inactive conformation of the CB 2 R. Here, we report the structure-based design of a novel bifunctional probe that captures the active conformation of the CB 2 R upon irradiation with light. An alkyne handle was incorporated to visualize the receptor using click-chemistry with fluorophore-azides. These probes may hold promise to study different receptor conformations in relation to their cellular localization and function., (© 2024 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Cannabinoid CB 2 receptor (CB 2 R) agonists are investigated as therapeutic agents in the clinic. However, their molecular mode-of-action is not fully understood. Here, we report the discovery of LEI-102, a CB 2 R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB 2 R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We identify key residues for CB 2 R activation. Highly lipophilic HU308 and the endocannabinoids, but not the more polar LEI-102, APD371, and CP55,940, reach the binding pocket through a membrane channel in TM1-TM7. Favorable physico-chemical properties of LEI-102 enable oral efficacy in a chemotherapy-induced nephropathy model. This study delineates the molecular mechanism of CB 2 R activation by selective agonists and highlights the role of lipophilicity in CB 2 R engagement. This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands., (© 2023. The Author(s).)