A critical pocket close to the glutamate binding site of mGlu receptors opens new possibilities for agonist design

Neuropharmacology
Francine AcherHugues-Olivier Bertrand

Abstract

A recent publication from Ogawa et al. suggested a possible allosteric chloride binding site in the extracellular domain of metabotropic glutamate receptors (mGluRs) by comparison with a similar site found in atrial natriuretic peptide receptor. We simultaneously reported about (S)-PCEP an agonist of subtype 4 mGluR that would bind to a similar pocket, adjacent to the glutamate binding site. Here we disclose LSP1-2093, a new derivative of (S)-PCEP that holds a nitrophenyl substituent. Docking experiments predict that the nitro group binds to the receptor at the putative chloride ion site. It is thus possible to take advantage of this putative chloride binding site to develop new types of mGluR agonists. This pocket is present in the structural family of Leucine Isoleucine Valine Binding Protein that includes class C GPCRs, suggesting that extended agonists may be identified at receptors bearing such a structural domain.

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Citations

Aug 27, 2015·Journal of Enzyme Inhibition and Medicinal Chemistry·Adriano MollicaEttore Novellino
May 5, 2012·Biochemical Pharmacology·Peter J Flor, Francine C Acher
Dec 3, 2014·Current Opinion in Pharmacology·Marianne Amalric
Jun 20, 2015·Molecular Pharmacology·John O DiRaddoJarda T Wroblewski
Jun 24, 2015·The Journal of Biological Chemistry·Patrick R GentryArthur Christopoulos
Jun 28, 2015·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Amélie S ToraCyril Goudet
Jan 11, 2020·Biochimica Et Biophysica Acta. Biomembranes·Charles M Thompson, Chih-Kai Chao
Feb 6, 2018·Journal of Medicinal Chemistry·Chelliah SelvamFrancine C Acher

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