2. Academic Validation
  3. Structure-Activity Relationship Study of the High-Affinity Neuropeptide Y4 Receptor Positive Allosteric Modulator VU0506013

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

  • J Med Chem. 2023 Jul 13;66(13):8745-8766. doi: 10.1021/acs.jmedchem.3c00383.
Corinna Schüß 1,  Oanh Vu 2,  Nigam M Mishra 3,  Iain R Tough 4,  Yu Du 5,  Jan Stichel 1,  Helen M Cox 4,  C David Weaver 5 6,  Jens Meiler 2 5 7,  Kyle A Emmitte 3,  Annette G Beck-Sickinger 1
Affiliations

Affiliations

  • 1 Institute of Biochemistry, Leipzig University, Leipzig 04103, Germany.
  • 2 Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.
  • 3 Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, Texas 76107, United States.
  • 4 King's College London, Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, London SE1 1UL, U.K.
  • 5 Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 6 Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 7 Institute for Drug Discovery, Leipzig University, Leipzig 04103, Germany.
PMID: 37339079 DOI: 10.1021/acs.jmedchem.3c00383
Abstract

Positive allosteric modulators targeting the Y4 receptor (Y4R), a G protein-coupled receptor (GPCR) involved in the regulation of satiety, offer great potential in anti-obesity research. In this study, we selected 603 compounds by using quantitative structure-activity relationship (QSAR) models and tested them in high-throughput screening (HTS). Here, the novel positive allosteric modulator (PAM) VU0506013 was identified, which exhibits nanomolar affinity and pronounced selectivity toward the Y4R in engineered cell lines and mouse descending colon mucosa natively expressing the Y4R. Based on this lead structure, we conducted a systematic SAR study in two regions of the scaffold and presented a series of 27 analogues with modifications in the N- and C-terminal heterocycles of the molecule to obtain insight into functionally relevant positions. By mutagenesis and computational docking, we present a potential binding mode of VU0506013 in the transmembrane core of the Y4R. VU0506013 presents a promising scaffold for developing in vivo tools to move toward anti-obesity drug research focused on the Y4R.

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