Identification and Characterization of the First Selective Y 4 Receptor Positive Allosteric Modulator

The human Y 4 receptor (Y 4 R) and its cognate ligand, pancreatic polypeptide (PP), are involved in the regulation of energy expenditure, satiety, and food intake. This system represents a potential target for the treatment of metabolic diseases and has been extensively investigated and validated in vivo. Here, we present the compound tBPC ( tert -butylphenoxycyclohexanol), a novel and selective Y 4 R positive allosteric modulator that potentiates Y 4 R activation in G-protein signaling and arrestin3 recruitment experiments. The compound has no effect on the binding of the orthosteric ligands, implying its allosteric mode of action at the Y 4 R and evidence for a purely efficacy-driven positive allosteric modulation. Finally, the ability of tBPC to selectively potentiate Y 4 R agonism initiated by PP was confirmed in mouse descending colon mucosa preparations expressing native Y 4 R, demonstrating Y 4 R positive allosteric modulation in vitro.