Structure-Activity Relationship Study of the High-Affinity Neuropeptide Y₄ Receptor Positive Allosteric Modulator VU0506013

Positiveallosteric modulators targeting the Y-4 receptor(Y4R), a G protein-coupled receptor (GPCR) involved inthe regulation of satiety, offer great potential in anti-obesity research.In this study, we selected 603 compounds by using quantitative structure-activityrelationship (QSAR) models and tested them in high-throughput screening(HTS). Here, the novel positive allosteric modulator (PAM) VU0506013was identified, which exhibits nanomolar affinity and pronounced selectivitytoward the Y4R in engineered cell lines and mouse descendingcolon mucosa natively expressing the Y4R. Based on thislead structure, we conducted a systematic SAR study in two regionsof the scaffold and presented a series of 27 analogues with modificationsin the N- and C-terminal heterocyclesof the molecule to obtain insight into functionally relevant positions.By mutagenesis and computational docking, we present a potential bindingmode of VU0506013 in the transmembrane core of the Y4R.VU0506013 presents a promising scaffold for developing invivo tools to move toward anti-obesity drug research focusedon the Y4R.