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

Schubert M, Stichel J, Du Y, Tough IR, Sliwoski G, Meiler J, Cox HM, Weaver CD, Beck-Sickinger AG
J Med Chem. 2017 60 (17): 7605-7612

PMID: 28795803 · DOI:10.1021/acs.jmedchem.7b00976

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

MeSH Terms (12)

Allosteric Regulation Animals Arrestins Chlorocebus aethiops COS Cells Cyclohexanols GTP-Binding Proteins HEK293 Cells Humans Models, Molecular Receptors, Neuropeptide Y Signal Transduction

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