Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
ACS Chem Neurosci
2018 Feb 21;92:306-319. doi: 10.1021/acschemneuro.7b00329.
Show Gene links
Show Anatomy links
A Novel Negative Allosteric Modulator Selective for GluN2C/2D-Containing NMDA Receptors Inhibits Synaptic Transmission in Hippocampal Interneurons.
Swanger SA, Vance KM, Acker TM, Zimmerman SS, DiRaddo JO, Myers SJ, Bundgaard C, Mosley CA, Summer SL, Menaldino DS, Jensen HS, Liotta DC, Traynelis SF.
???displayArticle.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.
Acker,
Mechanism for noncompetitive inhibition by novel GluN2C/D N-methyl-D-aspartate receptor subunit-selective modulators.
2011, Pubmed
Acker,
Mechanism for noncompetitive inhibition by novel GluN2C/D N-methyl-D-aspartate receptor subunit-selective modulators.
2011,
Pubmed Acker,
Structure-activity relationships and pharmacophore model of a noncompetitive pyrazoline containing class of GluN2C/GluN2D selective antagonists.
2013,
Pubmed Al-Hallaq,
NMDA di-heteromeric receptor populations and associated proteins in rat hippocampus.
2007,
Pubmed Brancaccio,
Astrocytes Control Circadian Timekeeping in the Suprachiasmatic Nucleus via Glutamatergic Signaling.
2017,
Pubmed Brickley,
NR2B and NR2D subunits coassemble in cerebellar Golgi cells to form a distinct NMDA receptor subtype restricted to extrasynaptic sites.
2003,
Pubmed Burzomato,
The receptor subunits generating NMDA receptor mediated currents in oligodendrocytes.
2010,
Pubmed Dubois,
Presynaptic GluN2D receptors detect glutamate spillover and regulate cerebellar GABA release.
2016,
Pubmed Faul,
G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences.
2007,
Pubmed Feng,
Allosteric modulation of NMDA receptors alters neurotransmission in the striatum of a mouse model of Parkinson's disease.
2014,
Pubmed Goebel,
NMDA receptor subunit gene expression in the rat brain: a quantitative analysis of endogenous mRNA levels of NR1Com, NR2A, NR2B, NR2C, NR2D and NR3A.
1999,
Pubmed
,
Xenbase Gonzalez,
NMDARs in neurological diseases: a potential therapeutic target.
2015,
Pubmed Hansen,
Implementation of a fluorescence-based screening assay identifies histamine H3 receptor antagonists clobenpropit and iodophenpropit as subunit-selective N-methyl-D-aspartate receptor antagonists.
2010,
Pubmed
,
Xenbase Hansen,
Distinct functional and pharmacological properties of Triheteromeric GluN1/GluN2A/GluN2B NMDA receptors.
2014,
Pubmed
,
Xenbase Hansen,
Structural and mechanistic determinants of a novel site for noncompetitive inhibition of GluN2D-containing NMDA receptors.
2011,
Pubmed
,
Xenbase Hildebrand,
GluN2B and GluN2D NMDARs dominate synaptic responses in the adult spinal cord.
2014,
Pubmed Hollmann,
Zinc potentiates agonist-induced currents at certain splice variants of the NMDA receptor.
1993,
Pubmed
,
Xenbase Huang,
Mg2+ block properties of triheteromeric GluN1-GluN2B-GluN2D NMDA receptors on neonatal rat substantia nigra pars compacta dopaminergic neurones.
2014,
Pubmed Jones,
Functional NR2B- and NR2D-containing NMDA receptor channels in rat substantia nigra dopaminergic neurones.
2005,
Pubmed Káradóttir,
NMDA receptors are expressed in oligodendrocytes and activated in ischaemia.
2005,
Pubmed Karakas,
Crystal structure of a heterotetrameric NMDA receptor ion channel.
2014,
Pubmed Karavanova,
Novel regional and developmental NMDA receptor expression patterns uncovered in NR2C subunit-beta-galactosidase knock-in mice.
2007,
Pubmed Khatri,
Structural determinants and mechanism of action of a GluN2C-selective NMDA receptor positive allosteric modulator.
2014,
Pubmed
,
Xenbase Kuner,
Multiple structural elements determine subunit specificity of Mg2+ block in NMDA receptor channels.
1996,
Pubmed
,
Xenbase Lee,
NMDA receptor structures reveal subunit arrangement and pore architecture.
2014,
Pubmed
,
Xenbase Li,
GRIN2D Recurrent De Novo Dominant Mutation Causes a Severe Epileptic Encephalopathy Treatable with NMDA Receptor Channel Blockers.
2016,
Pubmed Lozovaya,
Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model.
2014,
Pubmed Luo,
The majority of N-methyl-D-aspartate receptor complexes in adult rat cerebral cortex contain at least three different subunits (NR1/NR2A/NR2B).
1997,
Pubmed Mellone,
Modulation of NMDA receptor at the synapse: promising therapeutic interventions in disorders of the nervous system.
2013,
Pubmed Micu,
NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia.
2006,
Pubmed Monaghan,
Pharmacological modulation of NMDA receptor activity and the advent of negative and positive allosteric modulators.
2012,
Pubmed Monyer,
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.
1994,
Pubmed Mosley,
Quinazolin-4-one derivatives: A novel class of noncompetitive NR2C/D subunit-selective N-methyl-D-aspartate receptor antagonists.
2010,
Pubmed
,
Xenbase Mullasseril,
A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors.
2010,
Pubmed Ogden,
Contribution of the M1 transmembrane helix and pre-M1 region to positive allosteric modulation and gating of N-methyl-D-aspartate receptors.
2013,
Pubmed
,
Xenbase Ogden,
Potentiation of GluN2C/D NMDA receptor subtypes in the amygdala facilitates the retention of fear and extinction learning in mice.
2014,
Pubmed
,
Xenbase Parsons,
Extrasynaptic NMDA receptor involvement in central nervous system disorders.
2014,
Pubmed Pearlstein,
Glutamatergic synaptic currents of nigral dopaminergic neurons follow a postnatal developmental sequence.
2015,
Pubmed Perszyk,
GluN2D-Containing N-methyl-d-Aspartate Receptors Mediate Synaptic Transmission in Hippocampal Interneurons and Regulate Interneuron Activity.
2016,
Pubmed
,
Xenbase Piña-Crespo,
Subtypes of NMDA receptors in new-born rat hippocampal granule cells.
2002,
Pubmed Rauner,
Triheteromeric NR1/NR2A/NR2B receptors constitute the major N-methyl-D-aspartate receptor population in adult hippocampal synapses.
2011,
Pubmed Redrobe,
In vitro and in vivo characterisation of Lu AF64280, a novel, brain penetrant phosphodiesterase (PDE) 2A inhibitor: potential relevance to cognitive deficits in schizophrenia.
2014,
Pubmed Rumbaugh,
Exon 5 and spermine regulate deactivation of NMDA receptor subtypes.
2000,
Pubmed Salter,
NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury.
2005,
Pubmed Santangelo,
Novel NMDA receptor modulators: an update.
2012,
Pubmed Sheng,
Changing subunit composition of heteromeric NMDA receptors during development of rat cortex.
1994,
Pubmed Standaert,
Organization of N-methyl-D-aspartate glutamate receptor gene expression in the basal ganglia of the rat.
1994,
Pubmed Suryavanshi,
GluN2C/GluN2D subunit-selective NMDA receptor potentiator CIQ reverses MK-801-induced impairment in prepulse inhibition and working memory in Y-maze test in mice.
2014,
Pubmed Swanger,
NMDA Receptors Containing the GluN2D Subunit Control Neuronal Function in the Subthalamic Nucleus.
2015,
Pubmed Swanger,
Dendritic GluN2A synthesis mediates activity-induced NMDA receptor insertion.
2013,
Pubmed Tovar,
Triheteromeric NMDA receptors at hippocampal synapses.
2013,
Pubmed Tozzi,
Alpha-Synuclein Produces Early Behavioral Alterations via Striatal Cholinergic Synaptic Dysfunction by Interacting With GluN2D N-Methyl-D-Aspartate Receptor Subunit.
2016,
Pubmed Traynelis,
Software-based correction of single compartment series resistance errors.
1998,
Pubmed Traynelis,
Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit.
1998,
Pubmed
,
Xenbase Traynelis,
Control of proton sensitivity of the NMDA receptor by RNA splicing and polyamines.
1995,
Pubmed
,
Xenbase Traynelis,
Glutamate receptor ion channels: structure, regulation, and function.
2010,
Pubmed Vance,
NMDA receptors control vagal afferent excitability in the nucleus of the solitary tract.
2015,
Pubmed von Engelhardt,
GluN2D-containing NMDA receptors-mediate synaptic currents in hippocampal interneurons and pyramidal cells in juvenile mice.
2015,
Pubmed Wenzel,
NMDA receptor heterogeneity during postnatal development of the rat brain: differential expression of the NR2A, NR2B, and NR2C subunit proteins.
1997,
Pubmed Wenzel,
Developmental and regional expression of NMDA receptor subtypes containing the NR2D subunit in rat brain.
1996,
Pubmed Wu,
Memantine selectively blocks extrasynaptic NMDA receptors in rat substantia nigra dopamine neurons.
2015,
Pubmed Yamamoto,
Involvement of the N-methyl-D-aspartate receptor GluN2D subunit in phencyclidine-induced motor impairment, gene expression, and increased Fos immunoreactivity.
2013,
Pubmed Yuan,
Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases.
2015,
Pubmed Zhang,
Allosteric modulation of GluN2C/GluN2D-containing NMDA receptors bidirectionally modulates dopamine release: implication for Parkinson's disease.
2014,
Pubmed Zhang,
GluN2D-containing NMDA receptors inhibit neurotransmission in the mouse striatum through a cholinergic mechanism: implication for Parkinson's disease.
2014,
Pubmed Zimmerman,
Design, synthesis, and structure-activity relationship of a novel series of GluN2C-selective potentiators.
2014,
Pubmed
,
Xenbase
