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

• Type of Material: Article
• Authors: Sharon Swanger, Emory University; Katie M. Vance, Emory University; Timothy M. Acker, Emory University; Sommer S. Zimmerman, Emory University; John O. DiRaddo, Emory University; Scott J. Myers, Emory University; Christoffer Bundgaard, H. Lundbeck A/S; Cara A. Mosley, Emory University; Samamtja L. Summer, Emory University; David Menaldino, Emory University; Henrik S. Jensen, H. Lundbeck A/S; Dennis Liotta, Emory University; Stephen Traynelis, Emory University
• Language: English
• Date: 2018-02-01
• Publisher: American Chemical Society
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 American Chemical Society.
• Final Published Version (URL): http://dx.doi.org/10.1021/acschemneuro.7b00329
• Title of Journal or Parent Work: ACS Chemical Neuroscience
• ISSN: 1948-7193
• Volume: 9
• Issue: 2
• Start Page: 306
• End Page: 319
• Grant/Funding Information: NIH: NS036654 and NS065371 (SFT), F32-NS086368 and T32-DA015040 (SAS), F31-NS071802 (TMA), The Michael J. Fox Foundation (SFT).
• Keywords: negative allosteric modulator; GluN2C; Pharmacology & Pharmacy; Neurosciences; NEUROTRANSMISSION; Chemistry, Medicinal; DETERMINANTS; NAB-14; glutamate receptor; Biochemistry & Molecular Biology; SUBTYPES; REGIONAL EXPRESSION; Life Sciences & Biomedicine; SUBUNIT; RAT-BRAIN; NMDA receptor; MG2+ BLOCK; GluN2D; Science & Technology; Neurosciences & Neurology; NMDAR; MECHANISM; NONCOMPETITIVE INHIBITION; CURRENTS
• Research Categories: Health Sciences, Pharmacology; Biology, Neuroscience; Chemistry, Biochemistry

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.