A Novel Binding Mode Reveals Two Distinct Classes of NMDA Receptor GluN2B-selective Antagonists.
Stroebel, D., Buhl, D.L., Knafels, J.D., Chanda, P.K., Green, M., Sciabola, S., Mony, L., Paoletti, P., Pandit, J.(2016) Mol Pharmacol 89: 541-551
- PubMed: 26912815
- DOI: https://doi.org/10.1124/mol.115.103036
- Primary Citation of Related Structures:
5EWJ, 5EWL, 5EWM - PubMed 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.
Organizational Affiliation:
Ecole Normale Supérieure, PSL Research University, CNRS, INSERM, Institut de Biologie de l'École Normale Supérieure (IBENS), Paris, France (D.S., L.M., P.P.); Pfizer Worldwide Research and Development, Cambridge, Massachusetts (D.L.B., M.G., S.S.); and Pfizer Worldwide Research and Development, Groton, Connecticut (J.D.K., P.K.C., J.P.).