Glatthar, Ralf, Cristiano, Nunzia, Cabaye, Alexandre, Brabet, Isabelle, Tora, Amelie, Goudet, Cyril, Bertrand, Hugues-Olivier, Goupil-Lamy, Anne, Flor, Peter J, Pin, Jean-Philippe, McCort, Isabelle and Acher, Francine C (2024) Novel Inhibitory Site Revealed by XAP044 Mode of Action on the Metabotropic Glutamate 7 Receptor Venus Flytrap Domain. Journal of medicinal chemistry, 67 (14). pp. 11662-11687. ISSN 1520-4804

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.

Item Type:	Article
Keywords:	Receptors, Metabotropic Glutamate Humans Molecular Docking Simulation Structure-Activity Relationship Animals Protein Domains Allosteric Regulation HEK293 Cells Binding Sites
Date Deposited:	08 Aug 2024 00:46
Last Modified:	08 Aug 2024 00:46
URI:	https://oak.novartis.com/id/eprint/51550