Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Mol Pharmacol
2021 May 01;995:399-411. doi: 10.1124/molpharm.120.000218.
Show Gene links
Show Anatomy links
The Negative Allosteric Modulator EU1794-4 Reduces Single-Channel Conductance and Ca2+ Permeability of GluN1/GluN2A N-Methyl-d-Aspartate Receptors.
Perszyk RE
,
Zheng Z
,
Banke TG
,
Zhang J
,
Xie L
,
McDaniel MJ
,
Katzman BM
,
Pelly SC
,
Yuan H
,
Liotta DC
,
Traynelis SF
.
???displayArticle.abstract???
NMDA receptors are ligand-gated ion channels that mediate a slow, Ca2+-permeable component of excitatory synaptic currents. These receptors are involved in several important brain functions, including learning and memory, and have also been implicated in neuropathological conditions and acute central nervous system injury, which has driven therapeutic interest in their modulation. The EU1794 series of positive and negative allosteric modulators of NMDA receptors has structural determinants of action near the preM1 helix that is involved in channel gating. Here, we describe the effects of the negative allosteric modulator EU1794-4 on GluN1/GluN2A channels studied in excised outside-out patches. Coapplication of EU1794-4 with a maximally effective concentration of glutamate and glycine increases the fraction of time the channel is open by nearly 1.5-fold, yet reduces single-channel conductance by increasing access of the channel to several subconductance levels, which has the net overall effect of reducing the macroscopic current. The lack of voltage-dependence of negative modulation suggests this is unrelated to a channel block mechanism. As seen with other NMDA receptor modulators that reduce channel conductance, EU1794-4 also reduces the Ca2+ permeability relative to monovalent cations of GluN1/GluN2A receptors. We conclude that EU1794-4 is a prototype for a new class of NMDA receptor negative allosteric modulators that reduce both the overall current that flows after receptor activation and the flux of Ca2+ ion relative to monovalent cations. SIGNIFICANCE STATEMENT: NMDA receptors are implicated in many neurological conditions but are challenging to target given their ubiquitous expression. Several newly identified properties of the negative allosteric modulator EU1794-4, including reducing Ca2+ flux through NMDA receptors and attenuating channel conductance, explain why this modulator reduces but does not eliminate NMDA receptor function. A modulator with these properties could have therapeutic advantages for indications in which attenuation of NMDA receptor function is beneficial, such as neurodegenerative disease and acute injury.
Albers,
Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial.
2001, Pubmed
Albers,
Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial.
2001,
Pubmed
Amin,
NMDA Receptors Require Multiple Pre-opening Gating Steps for Efficient Synaptic Activity.
2021,
Pubmed
Amin,
A conserved glycine harboring disease-associated mutations permits NMDA receptor slow deactivation and high Ca2+ permeability.
2018,
Pubmed
Awad,
Predicting Death After Thrombectomy in the Treatment of Acute Stroke.
2020,
Pubmed
Baker,
Excitatory amino acids in cerebrospinal fluid following traumatic brain injury in humans.
1993,
Pubmed
Beal,
Mechanisms of excitotoxicity in neurologic diseases.
1992,
Pubmed
Benveniste,
Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis.
1984,
Pubmed
Blagrove,
The incidence of unpleasant dreams after sub-anaesthetic ketamine.
2009,
Pubmed
Bochevarov,
Multiconformation, Density Functional Theory-Based pKa Prediction in Application to Large, Flexible Organic Molecules with Diverse Functional Groups.
2016,
Pubmed
Bondoli,
Plasma and cerebrospinal fluid free amino acid concentration in post-traumatic cerebral oedema in patients with shock.
1981,
Pubmed
Bullock,
Factors affecting excitatory amino acid release following severe human head injury.
1998,
Pubmed
Burnashev,
Fractional calcium currents through recombinant GluR channels of the NMDA, AMPA and kainate receptor subtypes.
1995,
Pubmed
Choi,
Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists.
1988,
Pubmed
Crupi,
Management of Traumatic Brain Injury: From Present to Future.
2020,
Pubmed
Davis,
Termination of Acute Stroke Studies Involving Selfotel Treatment. ASSIST Steering Committed.
1997,
Pubmed
Diener,
Treatment of acute ischaemic stroke with the low-affinity, use-dependent NMDA antagonist AR-R15896AR. A safety and tolerability study.
2002,
Pubmed
Farin,
Lessons from epidemiologic studies in clinical trials of traumatic brain injury.
2004,
Pubmed
Gibb,
A structurally derived model of subunit-dependent NMDA receptor function.
2018,
Pubmed
Gladstone,
Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions.
2002,
Pubmed
Grotta,
Safety and tolerability of the glutamate antagonist CGS 19755 (Selfotel) in patients with acute ischemic stroke. Results of a phase IIa randomized trial.
1995,
Pubmed
Hansen,
Structural determinants of agonist efficacy at the glutamate binding site of N-methyl-D-aspartate receptors.
2013,
Pubmed
,
Xenbase
Jatzke,
Voltage and concentration dependence of Ca(2+) permeability in recombinant glutamate receptor subtypes.
2002,
Pubmed
Katayama,
Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury.
1990,
Pubmed
Katzman,
A novel class of negative allosteric modulators of NMDA receptor function.
2015,
Pubmed
Lai,
Excitotoxicity and stroke: identifying novel targets for neuroprotection.
2014,
Pubmed
Lees,
Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial. GAIN International Investigators.
2000,
Pubmed
Lees,
Cerestat and other NMDA antagonists in ischemic stroke.
1997,
Pubmed
Lewis,
Ion-concentration dependence of the reversal potential and the single channel conductance of ion channels at the frog neuromuscular junction.
1979,
Pubmed
Li,
De novo GRIN variants in NMDA receptor M2 channel pore-forming loop are associated with neurological diseases.
2019,
Pubmed
,
Xenbase
Lohmann,
The developmental stages of synaptic plasticity.
2014,
Pubmed
Monyer,
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.
1994,
Pubmed
Morris,
Failure of the competitive N-methyl-D-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: results of two phase III clinical trials. The Selfotel Investigators.
1999,
Pubmed
Muir,
Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists.
2006,
Pubmed
Nilsson,
Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats.
1990,
Pubmed
Olney,
Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate.
1969,
Pubmed
Paoletti,
NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease.
2013,
Pubmed
Parsons,
Extrasynaptic NMDA receptor involvement in central nervous system disorders.
2014,
Pubmed
Patel,
Hyperacute Management of Ischemic Strokes: JACC Focus Seminar.
2020,
Pubmed
Persson,
Chemical monitoring of neurosurgical intensive care patients using intracerebral microdialysis.
1992,
Pubmed
Perszyk,
An NMDAR positive and negative allosteric modulator series share a binding site and are interconverted by methyl groups.
2018,
Pubmed
,
Xenbase
Perszyk,
Biased modulators of NMDA receptors control channel opening and ion selectivity.
2020,
Pubmed
,
Xenbase
Premkumar,
Identification of a high affinity divalent cation binding site near the entrance of the NMDA receptor channel.
1996,
Pubmed
,
Xenbase
Premkumar,
Subconductance states of a mutant NMDA receptor channel kinetics, calcium, and voltage dependence.
1997,
Pubmed
,
Xenbase
Qureshi,
Extracellular glutamate and other amino acids in experimental intracerebral hemorrhage: an in vivo microdialysis study.
2003,
Pubmed
Rowland,
Subanesthetic ketamine: how it alters physiology and behavior in humans.
2005,
Pubmed
Sacco,
Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial.
2001,
Pubmed
Saver,
The 2012 Feinberg Lecture: treatment swift and treatment sure.
2013,
Pubmed
Schneggenburger,
Coupling of permeation and gating in an NMDA-channel pore mutant.
1997,
Pubmed
,
Xenbase
Shipton,
GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity.
2014,
Pubmed
Strong,
Distinct GluN1 and GluN2 Structural Determinants for Subunit-Selective Positive Allosteric Modulation of N-Methyl-d-aspartate Receptors.
2021,
Pubmed
Traynelis,
Getting the most out of noise in the central nervous system.
1998,
Pubmed
Traynelis,
Glutamate receptor ion channels: structure, regulation, and function.
2010,
Pubmed
Turner,
Acute ischemic stroke: improving access to intravenous tissue plasminogen activator.
2020,
Pubmed
Wagner,
Gender associations with cerebrospinal fluid glutamate and lactate/pyruvate levels after severe traumatic brain injury.
2005,
Pubmed
Warach,
Effect of the Glycine Antagonist Gavestinel on cerebral infarcts in acute stroke patients, a randomized placebo-controlled trial: The GAIN MRI Substudy.
2006,
Pubmed
Watanabe,
DRPEER: a motif in the extracellular vestibule conferring high Ca2+ flux rates in NMDA receptor channels.
2002,
Pubmed
,
Xenbase
Wollmuth,
Ion permeation in ionotropic glutamate receptors: Still dynamic after all these years.
2018,
Pubmed
Wood,
The NMDA receptor complex: a long and winding road to therapeutics.
2005,
Pubmed
Wroge,
Synaptic NMDA receptors mediate hypoxic excitotoxic death.
2012,
Pubmed
Wyllie,
Influence of GluN2 subunit identity on NMDA receptor function.
2013,
Pubmed
Wyllie,
Single-channel currents from recombinant NMDA NR1a/NR2D receptors expressed in Xenopus oocytes.
1996,
Pubmed
,
Xenbase
Yamamoto,
CSF and ECF glutamate concentrations in head injured patients.
1999,
Pubmed
Yelshanskaya,
Structural basis of AMPA receptor inhibition by trans-4-butylcyclohexane carboxylic acid.
2022,
Pubmed
Yi,
Properties of Triheteromeric N-Methyl-d-Aspartate Receptors Containing Two Distinct GluN1 Isoforms.
2018,
Pubmed
,
Xenbase
Yu,
Weighted Averaging Scheme and Local Atomic Descriptor for pKa Prediction Based on Density Functional Theory.
2018,
Pubmed
Yuan,
Context-dependent GluN2B-selective inhibitors of NMDA receptor function are neuroprotective with minimal side effects.
2015,
Pubmed
Yurkewicz,
The effect of the selective NMDA receptor antagonist traxoprodil in the treatment of traumatic brain injury.
2005,
Pubmed
Zheng,
Selectivity changes during activation of mutant Shaker potassium channels.
1997,
Pubmed
,
Xenbase
Zheng,
Intermediate conductances during deactivation of heteromultimeric Shaker potassium channels.
1998,
Pubmed
,
Xenbase