ArticleMolecular pharmacology2016
A Novel Binding Mode Reveals Two Distinct Classes of NMDA Receptor GluN2B-selective Antagonists.
Article in Molecular pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers, 1 of them a synthesis that pooled it.
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Who cites it
50 citing papers in PubMed, 1 synthesis or guideline pooled it, 103 citations in OpenAlex.
- Investigational Drugs for the Treatment of Depression (Part 2): Glutamatergic, Cholinergic, Sestrin Modulators, and Other Agents.Frontiers in pharmacology · 2022Pooled it
- Polarity-determined triple partition of dual binding pockets unlocks mechanistic insights and a novel antagonist design of NMDA receptors: a combined MD/DFT study.RSC advances · 2026Article
- Inhibition of GluN2B-containing N-methyl-D-aspartate receptors by radiprodil.Brain : a journal of neurology · 2026Article
- Anticonvulsant Potential of the Essential Oil ofACS omega · 2026Article
- GluN2B-specific NMDAR positive allosteric modulation reverses cognitive and behavioral abnormalities inScience advances · 2026Article
- Computational modeling for rational design of novel phenoxy tacrine derivatives targeting Alzheimer's disease.PloS one · 2026Article
- Article
- Ameliorative role of Polyscias fruticosa leaf extract in aluminum chloride-induced neurotoxicity flies possibly mediated by N-methyl-D-aspartate receptor antagonistic and anticholinesterase active compounds.Journal of natural medicines · 2025Article
- Accommodating Statistical and Physics-Based Computational Protocols for Molecular Glue Model and Evaluation.Journal of chemical information and modeling · 2025Article
- Drug Repurposing and Screening for Multiple Sclerosis Targeting Microglia and Macrophages.Molecular neurobiology · 2025Article
- Mechanistic Analysis of Decabromodiphenyl Ether-Induced Neurotoxicity in Humans Using Network Toxicology and Molecular Docking.Neurotoxicity research · 2025Article
- Hybrid derivatives containing dimethyl fumarate and benzothiazole scaffolds for the potential treatment of multiple sclerosis; in silico & in vivo study.Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences · 2024Article
- Review
- Mechanisms of NMDA Receptor Inhibition by Biguanide Compounds.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Reversible Control of Native GluN2B-Containing NMDA Receptors with Visible Light.ACS chemical neuroscience · 2024Article
- Article
- GluN2B subunit selective N-methyl-D-aspartate receptor ligands: Democratizing recent progress to assist the development of novel neurotherapeutics.Molecular diversity · 2024Review
- Structure and function of GluN1-3A NMDA receptor excitatory glycine receptor channel.Science advances · 2024Article
- Structural insights into NMDA receptor pharmacology.Biochemical Society transactions · 2023Review
- The pyridazine heterocycle in molecular recognition and drug discovery.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2023Review
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.