TY - JOUR T1 - A Novel Binding Mode Reveals Two Distinct Classes of NMDA Receptor GluN2B-selective Antagonists JF - Molecular Pharmacology JO - Mol Pharmacol SP - 541 LP - 551 DO - 10.1124/mol.115.103036 VL - 89 IS - 5 AU - David Stroebel AU - Derek L. Buhl AU - John D. Knafels AU - Pranab K. Chanda AU - Michael Green AU - Simone Sciabola AU - Laetitia Mony AU - Pierre Paoletti AU - Jayvardhan Pandit Y1 - 2016/05/01 UR - http://molpharm.aspetjournals.org/content/89/5/541.abstract N2 - 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. ER -