Identification and Characterization of the First Selective Y₄ Receptor Positive Allosteric Modulator

The human Y₄ receptor (Y₄R) 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 Y₄R positive allosteric modulator that potentiates Y₄R 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 Y₄R and evidence for a purely efficacy-driven positive allosteric modulation. Finally, the ability of tBPC to selectively potentiate Y₄R agonism initiated by PP was confirmed in mouse descending colon mucosa preparations expressing native Y₄R, demonstrating Y₄R positive allosteric modulation in vitro.