Probe and Assay Dependent Pharmacology of Dantrolene Analogues at the GPR35

The G-protein-coupled receptor 35 (GPR35) plays a key role in various physiological and pathological processes and has emerged as a potential therapeutic target for the treatment of pain, inflammation, and metabolic diseases. Herein, we report the discovery and characterization of dantrolene analogues as GPR35 ligands. Pharmacological profiling with label-free dynamic mass redistribution and Tango arrestin assays showed that the 2,4-imidazolidinedione-containing analogues of dantrolene act as partial agonists of the GPR35, while its urea, thiourea, or amido derivatives display probe and assay dependent antagonism against the receptor.