Differential binding properties of [3H]dextrorphan and [3H]MK-801 in heterologously expressed NMDA receptors

LePage, Keith T.; Ishmael, J.; Low, Chian-Ming; Traynelis, Stephen F.; Murray, Thomas F.

doi:10.1016/j.neuropharm.2005.01.029

Cited by 35 publications

(13 citation statements)

References 40 publications

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“…Furthermore, the inhibitory effect of YY-23 on the NMDA-induced current was not affected by membrane potential, and sustained administration of YY-23 inhibited [25,34] . This is entirely in contrast to the findings for the non-competitive antagonist, ketamine, as well as the uncompetitive channel blockers, memantine and MK-801 [25,34,[39][40][41][42] . MK-801 is poorly tolerated clinically due to its slow unblocking kinetics [34,43] .…”

Section: Discussioncontrasting

confidence: 94%

Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice

Zhang

Guo

et al. 2015

Acta Pharmacol Sin

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Aim: N-methyl-D-aspartic acid (NMDA) receptor modulators have shown promising results as potential antidepressant agents, whereas timosaponins extracted from the Chinese herb Rhizoma Anemarrhenae exhibit antidepressant activities. In the present study we examined whether YY-23, a modified metabolite of timosaponin B-III, could affect NMDA receptors in rat hippocampal neurons in vitro, and evaluated its antidepressant-like effects in stressed mice. Methods: NMDA-induced currents were recorded in acutely dissociated rat hippocampal CA1 neurons using a whole-cell recording technique. C57BL/6 mice were exposed to a 6-week chronic mild stress (CMS) or a 10-d chronic social defeat stress (CSDS). The stressed mice were treated with YY-23 (20 mg·kg -1 ·d -1 ) or a positive-control drug, fluoxetine (10 mg·kg -1 ·d -1 ) for 3 weeks. Behavioral assessments were carried out every week. Results: In acutely dissociated rat hippocampal CA1 neurons, YY-23 selectively and reversibly inhibited NMDA-induced currents with an EC 50 value of 2.8 μmol/L. This inhibition of NMDA-induced currents by YY-23 was non-competitive, and had no features of voltagedependency or use-dependency. Treatment of the stressed mice with YY-23 not only reversed CMS-induced deficiency of sucrose preference and immobility time, and CSDS-induced reduction of social interaction, but also had faster onset as compared to fluoxetine. Conclusion: YY-23 is a novel non-competitive antagonist of NMDA receptors with promising rapid antidepressant-like effects in mouse models of CMS and CSDS depression.

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Section: Discussioncontrasting

confidence: 94%

Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice

Zhang

Guo

et al. 2015

Acta Pharmacol Sin

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“…Amantadine is structurally very similar to memantine so is likely to interact with similar residues. In contrast, dextromethorphan's primary metabolite dextrorphan interacts with residues in the more extracellular portion of the vestibule . Our data suggest that this interaction is nonetheless altered by the GluN2A N615K variant deeper in the receptor pore.…”

Section: Discussionsupporting

confidence: 84%

The human NMDA receptor GluN2A^N615K variant influences channel blocker potency

Marwick

Skehel

Hardingham

et al. 2019

Pharmacology Res & Perspec

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N ‐methyl‐D‐aspartate (NMDA) receptors are glutamate receptors with key roles in synaptic plasticity, due in part to their Mg 2+ mediated voltage‐dependence. A large number of genetic variants affecting NMDA receptor subunits have been found in people with a range of neurodevelopmental disorders, including GluN2A N615K ( GRIN2A C1845A ) in two unrelated individuals with severe epileptic encephalopathy. This missense variant substitutes a lysine in place of an asparagine known to be important for blockade by Mg 2+ and other small molecule channel blockers. We therefore measured the impact of GluN2A N615K on a range of NMDA receptor channel blockers using two‐electrode voltage clamp recordings made in Xenopus oocytes. We found that GluN2A N615K resulted in block by Mg 2+ 1 mmol/L being greatly reduced (89% vs 8%), block by memantine 10 μmol/L (76% vs 27%) and amantadine 100 μmol/L (45% vs 17%) being substantially reduced, block by ketamine 10 μmol/L being modestly reduced (79% vs 73%) and block by dextromethorphan 10 μmol/L being enhanced (45% vs 55%). Coapplying Mg 2+ with memantine or amantadine did not reduce the GluN2A N615K block seen with either small molecule. In addition, we measured single–channel conductance of GluN2A N615K –containing NMDA receptors in outside‐out patches pulled from Xenopus oocytes, finding a 4‐fold reduction in conductance (58 vs 15 pS). In conclusion, the GluN2A N615K variant is associated with substantial changes to important physiological and pharmacological properties of the NMDA receptor. Our findings are consistent with GluN2A N615K having a disease–causing role, and inform potential therapeutic strategies.

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“…Assuming that equilibrium conditions were approached following 20 hours incubation times, these findings indicate ease of [ 3 H]GMOM binding to non‐stimulated, closed NMDA receptor conformations, relative to [ 3 H]MK‐801. Perhaps the recognition site for the binding of [ 3 H]GMOM to NMDA receptors is shallower than that of [ 3 H]MK‐801, similar to what has been reported for [ 3 H]dextrorphan . The differential regulation of the binding of [ 3 H]GMOM and [ 3 H]MK‐801 by orthosteric agonists/antagonists would be consistent with this suggestion.…”

Section: Discussionsupporting

confidence: 76%

Binding characterization of N‐(2‐chloro‐5‐thiomethylphenyl)‐N′‐(3‐[³H]₃methoxy phenyl)‐N′‐methylguanidine ([³H]GMOM), a non‐competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist

Metaxas

Berckel

Klein

et al. 2019

Pharmacology Res & Perspec

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Labeled with carbon‐11, N ‐(2‐chloro‐5‐thiomethylphenyl)‐ N ′‐(3‐methoxyphenyl)‐ N ′‐methylguanidine ([ 11 C]GMOM) is currently the only positron emission tomography (PET) tracer that has shown selectivity for the ion‐channel site of N ‐methyl‐D‐aspartate (NMDA) receptors in human imaging studies. The present study reports on the selectivity profile and in vitro binding properties of GMOM. The compound was screened on a panel of 80 targets, and labeled with tritium ([ 3 H]GMOM). The binding properties of [ 3 H]GMOM were compared to those of the reference ion‐channel ligand [ 3 H](+)‐dizocilpine maleate ([ 3 H]MK‐801), in a set of concentration‐response, homologous and heterologous inhibition, and association kinetics assays, performed with repeatedly washed rat forebrain preparations. GMOM was at least 70‐fold more selective for NMDA receptors compared to all other targets examined. In homologous inhibition and concentration‐response assays, the binding of [ 3 H]GMOM was regulated by NMDA receptor agonists, albeit in a less prominent manner compared to [ 3 H]MK‐801. Scatchard transformation of homologous inhibition data produced concave upward curves for [ 3 H]GMOM and [ 3 H]MK‐801. The radioligands showed bi‐exponential association kinetics in the presence of 100 μmol L −1 l ‐glutamate/30 μmol L −1 glycine. [ 3 H]GMOM (3 nmol L −1 and 10 nmol L −1 ) was inhibited with dual affinity by (+)‐MK‐801, ( R,S )‐ketamine and memantine, in both presence and absence of agonists. [ 3 H]MK‐801 (2 nmol L −1 ) was inhibited in a monophasic manner by GMOM under baseline and combined agonist conditions, with an IC 50 value of ~19 nmol L −1 . The non‐linear Scatchard plots, biphasic inhibition by open channel blockers, and bi‐exponential kinetics of [ 3 H]GMOM indicate a complex mechanism of interaction with the NMDA receptor ionophore. The implications for quantifying the PET signal of [ 11 C]GMOM are discussed.

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Differential binding properties of [3H]dextrorphan and [3H]MK-801 in heterologously expressed NMDA receptors

Cited by 35 publications

References 40 publications

Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice

Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice

The human NMDA receptor GluN2A^N615K variant influences channel blocker potency

Binding characterization of N‐(2‐chloro‐5‐thiomethylphenyl)‐N′‐(3‐[³H]₃methoxy phenyl)‐N′‐methylguanidine ([³H]GMOM), a non‐competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist

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Differential binding properties of [3H]dextrorphan and [3H]MK-801 in heterologously expressed NMDA receptors

Cited by 35 publications

References 40 publications

Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice

Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice

The human NMDA receptor GluN2AN615K variant influences channel blocker potency

Binding characterization of N‐(2‐chloro‐5‐thiomethylphenyl)‐N′‐(3‐[3H]3methoxy phenyl)‐N′‐methylguanidine ([3H]GMOM), a non‐competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist

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The human NMDA receptor GluN2A^N615K variant influences channel blocker potency

Binding characterization of N‐(2‐chloro‐5‐thiomethylphenyl)‐N′‐(3‐[³H]₃methoxy phenyl)‐N′‐methylguanidine ([³H]GMOM), a non‐competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist