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Abstract
N-methyl-d-aspartate receptors (NMDARs) are glutamate-gated ion channels that play key roles in brain physiology and pathology. Because numerous pathologic conditions involve NMDAR overactivation, subunit-selective antagonists hold strong therapeutic potential, although clinical successes remain limited. Among the most promising NMDAR-targeting drugs are allosteric inhibitors of GluN2B-containing receptors. Since the discovery of ifenprodil, a range of GluN2B-selective compounds with strikingly different structural motifs have been identified. This molecular diversity raises the possibility of distinct binding sites, although supporting data are lacking. Using X-ray crystallography, we show that EVT-101, a GluN2B antagonist structurally unrelated to the classic phenylethanolamine pharmacophore, binds at the same GluN1/GluN2B dimer interface as ifenprodil but adopts a remarkably different binding mode involving a distinct subcavity and receptor interactions. Mutagenesis experiments demonstrate that this novel binding site is physiologically relevant. Moreover, in silico docking unveils that GluN2B-selective antagonists broadly divide into two distinct classes according to binding pose. These data widen the allosteric and pharmacological landscape of NMDARs and offer a renewed structural framework for designing next-generation GluN2B antagonists with therapeutic value for brain disorders.
Footnotes
- Received December 19, 2015.
- Accepted February 22, 2016.
D.S. and D.L.B. (co-first) and P.P. and J.P. (co-senior) contributed equally to this work.
This work was supported by the Fondation pour la Recherche Médicale ["Equipe FRM" Grant DEQ2000326520 to P.P.] and by the French government ["Investissements d’Avenir" ANR-10-LABX-54 MEMOLIFE and ANR-11-IDEX-0001-02 PSL* Research University]. Use of the IMCA-CAT beamline 17- ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman-Woodward Medical Research Institute. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357.
This work was presented at the 45th Society for Neuroscience meeting (Program No. 383.25. 2015 Neuroscience Meeting Planner. Chicago, IL.).
D.S., L.M., and P.P. declare that they have no conflict of interest. P.K.C. is a former employee of Pfizer, Inc. J.D.K., S.S., D.L.B., M.G., and J.P. are currently employed by Pfizer, Inc.
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2016 The Author(s)
This is an open access article distributed under the CC-BY Attribution 4.0 International license.