2. Academic Validation
  3. Identification and Characterization of the First Selective Y4 Receptor Positive Allosteric Modulator

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

  • J Med Chem. 2017 Sep 14;60(17):7605-7612. doi: 10.1021/acs.jmedchem.7b00976.
Mario Schubert 1,  Jan Stichel 1,  Yu Du 2,  Iain R Tough 3,  Gregory Sliwoski 4,  Jens Meiler 4 5,  Helen M Cox 3,  C David Weaver 2 5,  Annette G Beck-Sickinger 1
Affiliations

Affiliations

  • 1 Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, Leipzig University , Leipzig 04103, Germany.
  • 2 Department of Pharmacology, Vanderbilt University , Nashville, Tennessee 37232, United States.
  • 3 Wolfson Centre for Age-Related Diseases, King's College London , Guy's Campus, London SE1 1UL, U.K.
  • 4 Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37235, United States.
  • 5 Vanderbilt Institute of Chemical Biology, Vanderbilt University , Nashville, Tennessee 37232, United States.
PMID: 28795803 DOI: 10.1021/acs.jmedchem.7b00976
Abstract

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.

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