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Molecular Pharmacology

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Research ArticleArticle

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 and Stephen F. Traynelis
Molecular Pharmacology November 2014, 86 (5) 548-560; DOI: https://doi.org/10.1124/mol.114.094516
Alpa Khatri
Pharmacology 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
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Pieter B. Burger
Pharmacology 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
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Sharon A. Swanger
Pharmacology 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
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Kasper B. Hansen
Pharmacology 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
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Sommer Zimmerman
Pharmacology 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
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Erkan Karakas
Pharmacology 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
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Dennis C. Liotta
Pharmacology 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
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Hiro Furukawa
Pharmacology 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
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James P. Snyder
Pharmacology 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
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Stephen F. Traynelis
Pharmacology 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
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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.

Footnotes

    • Received June 28, 2014.
    • Accepted September 9, 2014.
  • This work was supported by the National Institutes of Health National Institute of Neurologic Disorders and Stroke [Grants F32-NS078873, R01-NS065371], National Institute of Mental Health [Grant R21-MH094525], National Institute of General Medicine [Grants P20-GM103546, R01-GM105730], and the Michael J Fox Foundation.

  • Several of the authors (D.C.L., J.P.S., S.F.T., S.Z.) are coinventors on Emory University-owned intellectual property, board members (D.C.L.), or paid consultants for companies developing NMDAR modulators (S.F.T., K.B.H.).

  • dx.doi.org/10.1124/mol.114.094516.

  • ↵Embedded ImageThis article has supplemental material available at mol.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (5)
Molecular Pharmacology
Vol. 86, Issue 5
1 Nov 2014
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Research ArticleArticle

Analysis of a GluN2C NMDAR 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 and Stephen F. Traynelis
Molecular Pharmacology November 1, 2014, 86 (5) 548-560; DOI: https://doi.org/10.1124/mol.114.094516

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Research ArticleArticle

Analysis of a GluN2C NMDAR 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 and Stephen F. Traynelis
Molecular Pharmacology November 1, 2014, 86 (5) 548-560; DOI: https://doi.org/10.1124/mol.114.094516
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