Novel Ligands for the Orphan Receptor GPR151 Modulate Morphine Action.

GPR151 is an orphan G-protein-coupled receptor expressed on specific neurons. Its expression has been reported to be upregulated in the dorsal root ganglia in mouse nerve injury models, suggesting a role in pain transmission. We used our unique ligand screening system to identify novel agonists and partial agonists for GPR151. The novel ligands, GUM3 and GUM4, have the psoralen ring and exhibited agonist activity (EC50 = 4.1 ± 1.0 μM) and highly weak partial agonist activity (EC50 = 0.81 ± 1.46 μM), respectively, in the [35S]-GTPγS binding assay. Both ligands induced GPR151 internalization and increased reporter gene expression in Chinese hamster ovary cells transiently expressing human GPR151 upon ligand stimulation. Activity evaluation employing structural analogs provided insights into a series of ligand structure-activity relationships. Administration of the unique ligands had no effect on thermal hyperalgesia in rats; however, an agonist and a partial agonist enhanced and attenuated the analgesic effect of morphine, respectively, when co-administered. These findings not only reveal the physiological role of GPR151 in pain transmission but also demonstrate its potential as a novel drug target for pain control. Our findings indicate that the development of GPR151 ligands can contribute to the reduction of opioid use.