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Author Notes:

Corresponding author: Stephen F. Traynelis, Department of Pharmacology, 1510 Clifton Rd NE, Atlanta, GA 30322, strayne@emory.edu, phone: 404-727-1375.

SAS, KMV, TMA, SSZ, CH, SLS, DSM, HSJ, DCL, and SFT designed the research.

SAS, KMV, TMA, SSZ, JDO, CH, SJM, SLS, and CAM performed experiments and analyzed data.

SAS, KMV, TMA, SSZ, SLS, CH, DSM, HSJ, and SFT wrote the paper.

The authors thank the Emory Chemical Biology Discovery Center as well as Phuong Le and Jing Zhang for excellent technical assistance.

SFT is a consultant for Boehringer-Ingleheim Pharma GmbH and Janssen Pharmaceuticals Inc., is the principle investigator on a research grant from Janssen Pharmaceuticals Inc. to Emory University School of Medicine, is a member of the SAB for Sage Therapeuetics, and is co-founder of NeurOp Inc.

DCL is a member of the Board of Directors for NeurOp Inc.

DCL, SFT, SLS, DSM, TMA, SSZ, and CAM are co-inventors on Emory-owned intellectual property associated with allosteric modulators of NMDAR function.

Subjects:

Research Funding:

NIH: NS036654 and NS065371 (SFT), F32-NS086368 and T32-DA015040 (SAS), F31-NS071802 (TMA), The Michael J. Fox Foundation (SFT).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Chemistry, Medicinal
  • Neurosciences
  • Pharmacology & Pharmacy
  • Neurosciences & Neurology
  • NMDA receptor
  • NMDAR
  • glutamate receptor
  • GluN2C
  • GluN2D
  • negative allosteric modulator
  • NAB-14
  • NONCOMPETITIVE INHIBITION
  • REGIONAL EXPRESSION
  • MG2+ BLOCK
  • RAT-BRAIN
  • SUBUNIT
  • CURRENTS
  • MECHANISM
  • SUBTYPES
  • NEUROTRANSMISSION
  • DETERMINANTS

A Novel Negative Allosteric Modulator Selective for GIuN2C/2D-Containing NMDA Receptors Inhibits Synaptic Transmission in Hippocampal Interneurons

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Journal Title:

ACS Chemical Neuroscience

Volume:

Volume 9, Number 2

Publisher:

, Pages 306-319

Type of Work:

Article | Post-print: After Peer Review

Abstract:

N-Methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors that mediate excitatory synaptic transmission and have been implicated in numerous neurological disorders. NMDARs typically comprise two GluN1 and two GluN2 subunits. The four GluN2 subtypes (GluN2A-GluN2D) have distinct functional properties and gene expression patterns, which contribute to diverse functional roles for NMDARs in the brain. Here, we present a series of GluN2C/2D-selective negative allosteric modulators built around a N-aryl benzamide (NAB) core. The prototypical compound, NAB-14, is >800-fold selective for recombinant GluN2C/GluN2D over GluN2A/GluN2B in Xenopus oocytes and has an IC50 value of 580 nM at recombinant GluN2D-containing receptors expressed in mammalian cells. NAB-14 inhibits triheteromeric (GluN1/GluN2A/GluN2C) NMDARs with modestly reduced potency and efficacy compared to diheteromeric (GluN1/GluN2C/GluN2C) receptors. Site-directed mutagenesis suggests that structural determinants for NAB-14 inhibition reside in the GluN2D M1 transmembrane helix. NAB-14 inhibits GluN2D-mediated synaptic currents in rat subthalamic neurons and mouse hippocampal interneurons, but has no effect on synaptic transmission in hippocampal pyramidal neurons, which do not express GluN2C or GluN2D. This series possesses some druglike physical properties and modest brain permeability in rat and mouse. Altogether, this work identifies a new series of negative allosteric modulators that are valuable tools for studying GluN2C- and GluN2D-containing NMDAR function in brain circuits, and suggests that the series has the potential to be developed into therapies for selectively modulating brain circuits involving the GluN2C and GluN2D subunits.

Copyright information:

© 2017 American Chemical Society.

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