2. Academic Validation
  3. Novel Inhibitory Site Revealed by XAP044 Mode of Action on the Metabotropic Glutamate 7 Receptor Venus Flytrap Domain

Novel Inhibitory Site Revealed by XAP044 Mode of Action on the Metabotropic Glutamate 7 Receptor Venus Flytrap Domain

  • J Med Chem. 2024 May 1. doi: 10.1021/acs.jmedchem.3c01924.
Nunzia Cristiano 1,  Alexandre Cabayé 1 2,  Isabelle Brabet 3,  Ralf Glatthar 4,  Amelie Tora 3,  Cyril Goudet 3,  Hugues-Olivier Bertrand 2,  Anne Goupil-Lamy 2,  Peter J Flor 5,  Jean-Philippe Pin 3,  Isabelle McCort-Tranchepain 1,  Francine C Acher 1 6
Affiliations

Affiliations

  • 1 Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Cité, CNRS UMR 8601, 75006 Paris, France.
  • 2 BIOVIA Dassault Systèmes, F-78140 Vélizy-Villacoublay Cedex, France.
  • 3 Institute of Functional Genomics, University of Montpellier, CNRS, Inserm, 34094 Montpellier, France.
  • 4 Novartis Biomedical Research, CH-4002 Basel, Switzerland.
  • 5 Laboratory of Molecular and Cellular Neurobiology, Faculty of Biology and Preclinical Medicine, University of Regensburg, 93053 Regensburg, Germany.
  • 6 Saints-Pères Paris Institute for the Neurosciences, Université Paris Cité, CNRS UMR 8003, 75006 Paris, France.
PMID: 38691510 DOI: 10.1021/acs.jmedchem.3c01924
Abstract

Metabotropic glutamate (mGlu) receptors play a key role in modulating most synapses in the brain. The mGlu7 receptors inhibit presynaptic neurotransmitter release and offer therapeutic possibilities for post-traumatic stress disorders or epilepsy. Screening campaigns provided mGlu7-specific allosteric modulators as the inhibitor XAP044 (Gee et al. J. Biol. Chem. 2014). In contrast to other mGlu receptor allosteric modulators, XAP044 does not bind in the transmembrane domain but to the extracellular domain of the mGlu7 receptor and not at the orthosteric site. Here, we identified the mode of action of XAP044, combining synthesis of derivatives, modeling and docking experiments, and mutagenesis. We propose a unique mode of action of these inhibitors, preventing the closure of the Venus flytrap agonist binding domain. While acting as a noncompetitive antagonist of L-AP4, XAP044 and derivatives act as apparent competitive antagonists of LSP4-2022. These data revealed more potent XAP044 analogues and new possibilities to target mGluRs.

Figures
Products