GPR50 (also known as MMR, H9 or ML1X), is an orphan G protein-coupled receptor
belonging to the melatonin receptor family, but which has lost the ability to bind melatonin during evolution. Its endogenous ligand has not yet been identified. However, the role of GPR50 in the pathophysiology of various diseases has been described, such as major CNS diseases, major depression, and bipolar disorder. Moreover, recent findings showed that the orphan GPR50 receptor promotes constitutive transforming growth factor-β (TGF-β) receptor signaling and protects against cancer development. Herein the inventors identified the first potent agonists of the orphan GPR50 receptor in a functional cAMP assay. Among these agonist, the 5-methoxy-2-methyl indole (Cp15) which displayed a high agonistic activity at GPR50 receptor (EC50 = 0.5 nM, Kd <1nM). Intriguingly, replacement of the methyl group in the initially screened 5-methoxy-2-methyl indole with a 2-methylamino group (5-methoxy-2-methylamine indole) (Cp32) resulted in also high agonist potency. In another contribution to define SARs, indole nucleus of Cp15 was replaced by benzofuran (Cp34).