Discovery of Small-Molecule Modulators of the Human Y(4) Receptor

The human neuropeptide Y(4) receptor (Y(4)R) and its native ligand, pancreatic polypeptide, are critically involved in the regulation of human metabolism by signaling satiety and regulating food intake, as well as increasing energy expenditure. Thus, this receptor represents a putative target for treatment of obesity. With respect to new approaches to treat complex metabolic disorders, especially in multi-receptor systems, small molecule allosteric modulators have been in the focus of research in the last years. However, no positive allosteric modulators or agonists of the Y(4)R have been described so far. In this study, small molecule compounds derived from the Niclosamide scaffold were identified by high-throughput screening to increase Y(4)R activity. Compounds were characterized for their potency and their effects at the human Y(4)R and as well as their selectivity towards Y(1)R, Y(2)R and Y(5)R. These compounds provide a structure-activity relationship profile around this common scaffold and lay the groundwork for hit-to-lead optimization and characterization of positive allosteric modulators of the Y(4)R.