Discovery of Small Molecule Ligands Targeting Orphan G Protein-Coupled Receptors GPR3, GPR6, and GPR12

GPR3, GPR6, and GPR12 form a subfamily of Class A orphan G protein-coupled receptors (oGPCRs), for which endogenous ligands have not been identified. Despite their high sequence similarity, each receptor exhibits unique expression profiles in human tissues. Their physiological roles and therapeutic potential are gradually being understood, indicating their critical involvement in various diseases, including central nervous system (CNS) disorders, metabolic diseases, and cancer. Notably, the GPR6 inverse agonist CVN424 is currently in Phase III clinical trials for the treatment of Parkinson’s disease (PD). The recent determination of high-resolution structures of GPR3, GPR6, and GPR12 has significantly enhanced their attractiveness as emerging therapeutic targets for drug discovery. Herein, we summarize the current understanding of the structural and functional characteristics of GPR3, GPR6, and GPR12. We further highlight recent progress in relevant ligand discovery and discuss the key challenges and opportunities in developing potent and selective modulators targeting these orphan receptors.