Structure-Activity Relationship Study of the High-Affinity Neuropeptide Y Receptor Positive Allosteric Modulator VU0506013.

Positive allosteric modulators targeting the Y receptor (YR), a G protein-coupled receptor (GPCR) involved in the regulation of satiety, offer great potential in anti-obesity research. In this study, we selected 603 compounds by using quantitative structure-activity relationship (QSAR) models and tested them in high-throughput screening (HTS). Here, the novel positive allosteric modulator (PAM) VU0506013 was identified, which exhibits nanomolar affinity and pronounced selectivity toward the YR in engineered cell lines and mouse descending colon mucosa natively expressing the YR. Based on this lead structure, we conducted a systematic SAR study in two regions of the scaffold and presented a series of 27 analogues with modifications in the - and -terminal heterocycles of the molecule to obtain insight into functionally relevant positions. By mutagenesis and computational docking, we present a potential binding mode of VU0506013 in the transmembrane core of the YR. VU0506013 presents a promising scaffold for developing tools to move toward anti-obesity drug research focused on the YR.