Discovery of a Photoaffinity Probe that Captures the Active Conformation of the Cannabinoid CB₂ Receptor

The cannabinoid receptor type 2 (CB₂R) 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 CB₂R. Here, we report the structure-based design of a novel bifunctional probe that captures the active conformation of the CB₂R 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.