Development of Ligands for the Super Conserved Orphan G Protein-Coupled Receptor GPR27 with Improved Efficacy and Potency.

The orphan G protein-coupled receptor GPR27 appears to play a role in insulin production, secretion, lipid metabolism, neuronal plasticity, and l-lactate homeostasis. However, investigations on the function of GPR27 are impaired by the lack of potent and efficacious agonists. We describe herein the development of di- and trisubstituted benzamide derivatives 4a - e , 7a - z , and 7aa - ai , which display GPR27-specific activity in a β-arrestin 2 recruitment-based assay. Highlighted compounds are PT-91 ( 7p : pEC 50 6.15; E max 100%) and 7ab (pEC 50 6.56; E max 99%). A putative binding mode was revealed by the docking studies of 7p and 7ab with a GPR27 homology model. The novel active compounds exhibited no GPR27-mediated activation of G proteins, indicating that the receptor may possess an atypical profile. Compound 7p displays high metabolic stability and brain exposure in mice. Thus, 7p represents a novel tool to investigate the elusive pharmacology of GPR27 and assess its potential as a drug target.