ArticleThe Journal of biological chemistry2013
Crystal structure and pharmacological characterization of a novel N-methyl-D-aspartate (NMDA) receptor antagonist at the GluN1 glycine binding site.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 31 citations in OpenAlex.
- Structural and mechanistic insights into gating and allosteric modulation of GluN1-GluN3A NMDA receptors.Nature structural & molecular biology · 2026Article
- N-Methyl-D-aspartate receptors: structure, signaling and roles in atherosclerosis.Journal of translational medicine · 2026Review
- Discrete interneuron subsets participate in GluN1/GluN3A excitatory glycine receptor (eGlyR)-mediated regulation of hippocampal network activity throughout development and evolution.Research square · 2025Article
- Discrete interneuron subsets participate in GluN1/GluN3A excitatory glycine receptor (eGlyR)-mediated regulation of hippocampal network activity throughout development and evolution.bioRxiv : the preprint server for biology · 2025Article
- German Chamomile (International journal of molecular sciences · 2024Article
- NMDA Receptor Antagonists: Emerging Insights into Molecular Mechanisms and Clinical Applications in Neurological Disorders.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Structural prediction of GluN3 NMDA receptors.Frontiers in physiology · 2024Article
- Structural insights into NMDA receptor pharmacology.Biochemical Society transactions · 2023Review
- Allosteric modulation of GluN1/GluN3 NMDA receptors by GluN1-selective competitive antagonists.The Journal of general physiology · 2023Article
- The combination of Astragalus membranaceus and ligustrazine mitigates cerebral ischemia-reperfusion injury via regulating NR2B-ERK/CREB signaling.Brain and behavior · 2023Article
- Revealing the contribution of astrocytes to glutamatergic neuronal transmission.Frontiers in cellular neuroscience · 2022Review
- Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.Pharmacological reviews · 2021Review
- Negative allosteric modulation of GluN1/GluN3 NMDA receptors.Neuropharmacology · 2020Article
- Structure, function, and allosteric modulation of NMDA receptors.The Journal of general physiology · 2018Review
- Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- The low binding affinity of D-serine at the ionotropic glutamate receptor GluD2 can be attributed to the hinge region.Scientific reports · 2017Article
- Computationally Discovered Potentiating Role of Glycans on NMDA Receptors.Scientific reports · 2017Article
- Guidelines for the successful generation of protein-ligand complex crystals.Acta crystallographica. Section D, Structural biology · 2017Review
- Prediction of N-Methyl-D-Aspartate Receptor GluN1-Ligand Binding Affinity by a Novel SVM-Pose/SVM-Score Combinatorial Ensemble Docking Scheme.Scientific reports · 2017Article
- Antinociceptive Activity ofFrontiers in pharmacology · 2017Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
NMDA receptors are ligand-gated ion channels that mediate excitatory neurotransmission in the brain. They are tetrameric complexes composed of glycine-binding GluN1 and GluN3 subunits together with glutamate-binding GluN2 subunits. Subunit-selective antagonists that discriminate between the glycine sites of GluN1 and GluN3 subunits would be valuable pharmacological tools for studies on the function and physiological roles of NMDA receptor subtypes. In a virtual screening for antagonists that exploit differences in the orthosteric binding site of GluN1 and GluN3 subunits, we identified a novel glycine site antagonist, 1-thioxo-1,2-dihydro-[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one (TK40). Here, we show by Schild analysis that TK40 is a potent competitive antagonist with Kb values of 21-63 nM at the GluN1 glycine-binding site of the four recombinant GluN1/N2A-D receptors. In addition, TK40 displayed >100-fold selectivity for GluN1/N2 NMDA receptors over GluN3A- and GluN3B-containing NMDA receptors and no appreciable effects at AMPA receptors. Binding experiments on rat brain membranes and the purified GluN1 ligand-binding domain using glycine site GluN1 radioligands further confirmed the competitive interaction and high potency. To delineate the binding mechanism, we have solved the crystal structure of the GluN1 ligand-binding domain in complex with TK40 and show that TK40 binds to the orthosteric binding site of the GluN1 subunit with a binding mode that was also predicted by virtual screening. Furthermore, the structure reveals that the imino acetamido group of TK40 acts as an α-amino acid bioisostere, which could be of importance in bioisosteric replacement strategies for future ligand design.
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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.