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

• Published in: Chembiochem : a European journal of chemical biology Vol. 25; no. 7; pp. e202300785 - n/a
• Main Authors: De Paus, Laura V., An, Yu, Janssen, Antonius P. A., Berg, Richard J. B. H. N., Heitman, Laura H., Stelt, Mario
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 02.04.2024; Wiley Subscription Services, Inc
• Subjects: affinity-based protein profiling; Alkynes; Biochemistry & Molecular Biology; cannabinoid CB2 receptor; Cannabinoid CB2 receptors; Cannabinoids; Chemistry, Medicinal; Fluorescent indicators; GPCR; Inflammatory diseases; Irradiation; Life Sciences & Biomedicine; Localization; Pharmacology & Pharmacy; Photoaffinity-based probe; Probes; Receptors; Science & Technology; GPCR; Photoaffinity-based probe; affinity-based protein profiling; cannabinoid CB2 receptor
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.202300785

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. We present a series of bifunctional photoaffinity CB2R selective probes based on the 5‐fluoropyridin‐2‐yl‐benzyl‐imidazoleidine‐2,4‐dione derivative LEI‐102, with both inverse agonist and partial agonist behaviour in vitro. These photoaffinity probes have improved affinity and potency compared to previously published LEI‐121.