Evidence map›Paper›PMID 25205677›Full record

ArticleMolecular pharmacology2014

Structural determinants and mechanism of action of a GluN2C-selective NMDA receptor positive allosteric modulator.

Alpa Khatri, Pieter B Burger, Sharon A Swanger, Kasper B Hansen, Sommer Zimmerman, Erkan Karakas, Dennis C Liotta, Hiro Furukawa, James P Snyder, Stephen F Traynelis

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.

0numbers the graph read from it
0cells of the map it votes in
51citing papers in PubMed
3.2field-weighted citation impact, top 8% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

51 citing papers in PubMed, 77 citations in OpenAlex.

  1. Review
  2. Review
  3. Article
  4. Article
  5. Review
  6. Article
  7. Article
  8. Article
  9. Therapeutic potential of N-methyl-D-aspartate receptor modulators in psychiatry.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024
    Review
  10. Selective Cell-Surface Expression of Triheteromeric NMDA Receptors.Methods in molecular biology (Clifton, N.J.) · 2024
    Article
  11. Article
  12. Biological chemistry · 2023
    Article
  13. Review
  14. Article
  15. Membrane Stretch Gates NMDA Receptors.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022
    Article
  16. NaNeurobiology of disease · 2022
    Article
  17. Review
  18. Article
  19. Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 3 institutions in 1 country.

Alpa KhatriPharmacology Department (A.K., S.A.S., S.F.T.) and Chemistry Department (S.Z., P.B.B., D.C.L., J.P.S.), Emory University, Atlanta, Georgia; Department of Biomedical and Pharmaceutical Sciences, and Center for Biomolecular Structure and Dynamics (K.B.H.), University of Montana, Missoula, Montana; and Cold Spring Harbor Laboratories (E.K., H.F.), Cold Spring Harbor, New York.
Pieter B BurgerPharmacology Department (A.K., S.A.S., S.F.T.) and Chemistry Department (S.Z., P.B.B., D.C.L., J.P.S.), Emory University, Atlanta, Georgia; Department of Biomedical and Pharmaceutical Sciences, and Center for Biomolecular Structure and Dynamics (K.B.H.), University of Montana, Missoula, Montana; and Cold Spring Harbor Laboratories (E.K., H.F.), Cold Spring Harbor, New York.
Sharon A SwangerPharmacology Department (A.K., S.A.S., S.F.T.) and Chemistry Department (S.Z., P.B.B., D.C.L., J.P.S.), Emory University, Atlanta, Georgia; Department of Biomedical and Pharmaceutical Sciences, and Center for Biomolecular Structure and Dynamics (K.B.H.), University of Montana, Missoula, Montana; and Cold Spring Harbor Laboratories (E.K., H.F.), Cold Spring Harbor, New York.
Kasper B HansenPharmacology Department (A.K., S.A.S., S.F.T.) and Chemistry Department (S.Z., P.B.B., D.C.L., J.P.S.), Emory University, Atlanta, Georgia; Department of Biomedical and Pharmaceutical Sciences, and Center for Biomolecular Structure and Dynamics (K.B.H.), University of Montana, Missoula, Montana; and Cold Spring Harbor Laboratories (E.K., H.F.), Cold Spring Harbor, New York.
Sommer ZimmermanPharmacology Department (A.K., S.A.S., S.F.T.) and Chemistry Department (S.Z., P.B.B., D.C.L., J.P.S.), Emory University, Atlanta, Georgia; Department of Biomedical and Pharmaceutical Sciences, and Center for Biomolecular Structure and Dynamics (K.B.H.), University of Montana, Missoula, Montana; and Cold Spring Harbor Laboratories (E.K., H.F.), Cold Spring Harbor, New York.
Erkan KarakasPharmacology Department (A.K., S.A.S., S.F.T.) and Chemistry Department (S.Z., P.B.B., D.C.L., J.P.S.), Emory University, Atlanta, Georgia; Department of Biomedical and Pharmaceutical Sciences, and Center for Biomolecular Structure and Dynamics (K.B.H.), University of Montana, Missoula, Montana; and Cold Spring Harbor Laboratories (E.K., H.F.), Cold Spring Harbor, New York.
Dennis C LiottaPharmacology Department (A.K., S.A.S., S.F.T.) and Chemistry Department (S.Z., P.B.B., D.C.L., J.P.S.), Emory University, Atlanta, Georgia; Department of Biomedical and Pharmaceutical Sciences, and Center for Biomolecular Structure and Dynamics (K.B.H.), University of Montana, Missoula, Montana; and Cold Spring Harbor Laboratories (E.K., H.F.), Cold Spring Harbor, New York.
Hiro FurukawaPharmacology Department (A.K., S.A.S., S.F.T.) and Chemistry Department (S.Z., P.B.B., D.C.L., J.P.S.), Emory University, Atlanta, Georgia; Department of Biomedical and Pharmaceutical Sciences, and Center for Biomolecular Structure and Dynamics (K.B.H.), University of Montana, Missoula, Montana; and Cold Spring Harbor Laboratories (E.K., H.F.), Cold Spring Harbor, New York.
James P SnyderPharmacology Department (A.K., S.A.S., S.F.T.) and Chemistry Department (S.Z., P.B.B., D.C.L., J.P.S.), Emory University, Atlanta, Georgia; Department of Biomedical and Pharmaceutical Sciences, and Center for Biomolecular Structure and Dynamics (K.B.H.), University of Montana, Missoula, Montana; and Cold Spring Harbor Laboratories (E.K., H.F.), Cold Spring Harbor, New York.
Stephen F TraynelisPharmacology Department (A.K., S.A.S., S.F.T.) and Chemistry Department (S.Z., P.B.B., D.C.L., J.P.S.), Emory University, Atlanta, Georgia; Department of Biomedical and Pharmaceutical Sciences, and Center for Biomolecular Structure and Dynamics (K.B.H.), University of Montana, Missoula, Montana; and Cold Spring Harbor Laboratories (E.K., H.F.), Cold Spring Harbor, New York strayne@emory.edu.
University of Montana · USCold Spring Harbor Laboratory · USEmory University · US

Funding

Surveillance genome sequencing to detect SARS-CoV-2 virus variants in MontanaP20GM103546 · NIGMS · UNIVERSITY OF MONTANA · PI BOWLER, BRUCE E · 2012 to 2021
$19.2M
Mechanism of Action of Novel Subunit-Selective NMDA Receptor ModulatorsR01NS065371 · NINDS · EMORY UNIVERSITY · PI TRAYNELIS, STEPHEN F · 2009 to 2018
$3.4M
STRUCTURE AND FUNCTION OF HETERO-MULTIMERIC GLUTAMATE RECEPTORSR01GM105730 · NIGMS · COLD SPRING HARBOR LABORATORY · PI FURUKAWA, HIROYASU · 2014 to 2017
$2.0M
Optimization of small molecule probesR21MH094525 · NIMH · EMORY UNIVERSITY · PI TRAYNELIS, STEPHEN F · 2012 to 2013
$458k
Mechanism of action of novel GluN2C NMDA receptor potentiatorsF32NS078873 · NINDS · EMORY UNIVERSITY · PI KHATRI, ALPA · 2012 to 2013
$106k
NIGMS NIH HHS P20 GM103546NIGMS NIH HHS P20-GM103546NIGMS NIH HHS R01 GM105730NIGMS NIH HHS R01-GM105730NIMH NIH HHS R21 MH094525NIMH NIH HHS R21-MH094525NINDS NIH HHS F32 NS078873NINDS NIH HHS F32-NS078873NINDS NIH HHS R01 NS065371
6 · The paper itself

Abstract

NMDA receptors are tetrameric complexes of GluN1, GluN2A-D, and GluN3A-B subunits and are involved in normal brain function and neurologic disorders. We identified a novel class of stereoselective pyrrolidinone (PYD) positive allosteric modulators for GluN2C-containing NMDA receptors, exemplified by methyl 4-(3-acetyl-4-hydroxy-1-[2-(2-methyl-1H-indol-3-yl)ethyl]-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate. Here we explore the site and mechanism of action of a prototypical analog, PYD-106, which at 30 μM does not alter responses of NMDA receptors containing GluN2A, GluN2B, and GluN2D and has no effect on AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid] and kainate receptors. Coapplication of 50 μM PYD-106 with a maximally effective concentration of glutamate and glycine increases the response of GluN1/GluN2C NMDA receptors in HEK-293 cells to 221% of that obtained in the absence of PYD (taken as 100%). Evaluation of the concentration dependence of this enhancement revealed an EC50 value for PYD of 13 μM. PYD-106 increased opening frequency and open time of single channel currents activated by maximally effective concentrations of agonist but only had modest effects on glutamate and glycine EC50. PYD-106 selectively enhanced the responses of diheteromeric GluN1/GluN2C receptors but not triheteromeric GluN1/GluN2A/GluN2C receptors. Inclusion of residues encoded by GluN1-exon 5 attenuated the effects of PYD. Three GluN2C residues (Arg194, Ser470, Lys470), at which mutagenesis virtually eliminated PYD function, line a cavity at the interface of the ligand binding and the amino terminal domains in a homology model of GluN1/GluN2C built from crystallographic data on GluN1/GluN2B. We propose that this domain interface constitutes a new allosteric modulatory site on the NMDA receptor.

Indexed as

Allosteric RegulationAnimalsBinding SitesCell LineGlutamic AcidGlycineHEK293 CellsHumansRatsReceptors, N-Methyl-D-AspartateStructure-Activity RelationshipXenopus laevisGlutamic AcidGlycineNR2C NMDA receptorReceptors, N-Methyl-D-Aspartate

Identifiers

PMID25205677
PMCPMC4201136
OpenAlexW2142978864

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

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.