ArticleeLife2018
An NMDAR positive and negative allosteric modulator series share a binding site and are interconverted by methyl groups.
Article in eLife, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- GluN2B-specific NMDAR positive allosteric modulation reverses cognitive and behavioral abnormalities inScience advances · 2026Article
- Selective enhancement of the interneuron network and gamma-band power via GluN2C/GluN2D NMDA receptor potentiation.The Journal of physiology · 2025Article
- Selective Reduction of CaMolecular neurobiology · 2024Article
- NMDA Receptor Antagonists: Emerging Insights into Molecular Mechanisms and Clinical Applications in Neurological Disorders.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Calcium- and calmodulin-dependent inhibition of NMDA receptor currents.Biophysical journal · 2024Review
- Therapeutic potential of N-methyl-D-aspartate receptor modulators in psychiatry.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Review
- Development of a Dihydroquinoline-Pyrazoline GluN2C/2D-Selective Negative Allosteric Modulator of theACS chemical neuroscience · 2023Article
- Novel neuroactive steroids as positive allosteric modulators of NMDA receptors: mechanism, site of action, and rescue pharmacology on GRIN variants associated with neurological conditions.Cellular and molecular life sciences : CMLS · 2023Article
- Complex functional phenotypes of NMDA receptor disease variants.Molecular psychiatry · 2022Article
- Targeting NMDA receptors in neuropsychiatric disorders by drug screening on human neurons derived from pluripotent stem cells.Translational psychiatry · 2022Review
- Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.Pharmacological reviews · 2021Review
- TwoeLife · 2021Article
- The Negative Allosteric Modulator EU1794-4 Reduces Single-Channel Conductance and CaMolecular pharmacology · 2021Article
- NMDA Receptors Require Multiple Pre-opening Gating Steps for Efficient Synaptic Activity.Neuron · 2021Article
- Distinct GluN1 and GluN2 Structural Determinants for Subunit-Selective Positive Allosteric Modulation ofACS chemical neuroscience · 2021Article
- Molecular Dynamics Simulation Techniques as Tools in Drug Discovery and Pharmacology: A Focus on Allosteric Drugs.Methods in molecular biology (Clifton, N.J.) · 2021Article
- NMDA receptor modulation and severe acute respiratory syndrome treatment.F1000Research · 2021Article
- From bedside-to-bench: What disease-associated variants are teaching us about the NMDA receptor.The Journal of physiology · 2021Review
- Negative allosteric modulation of GluN1/GluN3 NMDA receptors.Neuropharmacology · 2020Article
- Hodgkin-Huxley-Katz Prize Lecture: Genetic and pharmacological control of glutamate receptor channel through a highly conserved gating motif.The Journal of physiology · 2020Article
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11 authors.
Funding
Abstract
N-methyl-d-aspartate receptors (NMDARs) are an important receptor in the brain and have been implicated in multiple neurological disorders. Many non-selective NMDAR-targeting drugs are poorly tolerated, leading to efforts to target NMDAR subtypes to improve the therapeutic index. We describe here a series of negative allosteric NMDAR modulators with submaximal inhibition at saturating concentrations. Modest changes to the chemical structure interconvert negative and positive modulation. All modulators share the ability to enhance agonist potency and are use-dependent, requiring the binding of both agonists before modulators act with high potency. Data suggest that these modulators, including both enantiomers, bind to the same site on the receptor and share structural determinants of action. Due to the modulator properties, submaximal negative modulators in this series may spare NMDAR at the synapse, while augmenting the response of NMDAR in extrasynaptic spaces. These modulators could serve as useful tools to probe the role of extrasynaptic NMDARs.
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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.