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.
Neuropharmacology
2017 Oct 01;125:64-79. doi: 10.1016/j.neuropharm.2017.07.007.
Show Gene links
Show Anatomy links
Mechanism and properties of positive allosteric modulation of N-methyl-d-aspartate receptors by 6-alkyl 2-naphthoic acid derivatives.
Sapkota K
,
Irvine MW
,
Fang G
,
Burnell ES
,
Bannister N
,
Volianskis A
,
Culley GR
,
Dravid SM
,
Collingridge GL
,
Jane DE
,
Monaghan DT
.
???displayArticle.abstract???
The theory that N-methyl-d-aspartate receptor (NMDAR) hypofunction is responsible for the symptoms of schizophrenia is well supported by many pharmacological and genetic studies. Accordingly, positive allosteric modulators (PAMs) that augment NMDAR signaling may be useful for treating schizophrenia. Previously we have identified several NMDAR PAMs containing a carboxylic acid attached to naphthalene, phenanthrene, or coumarin ring systems. In this study, we describe several functional and mechanistic properties of UBP684, a 2-naphthoic acid derivative, which robustly potentiates agonist responses at each of the four GluN1a/GluN2 receptors and at neuronal NMDARs. UBP684 increases the maximal l-glutamate/glycine response while having minor subunit-specific effects on agonist potency. PAM binding is independent of agonist binding, and PAM activity is independent of membrane voltage, redox state, and the GluN1 exon 5 N-terminal insert. UBP684 activity is, however, markedly pH-dependent, with greater potentiation occurring at lower pHs and inhibitory activity at pH 8.4. UBP684 increases channel open probability (Po) and slows receptor deactivation time upon removal of l-glutamate, but not glycine. The structurally related PAM, UBP753, reproduced most of these findings, but did not prolong agonist removal deactivation time. Studies using cysteine mutants to lock the GluN1 and GluN2 ligand-binding domains (LBDs) in the agonist-bound states indicate that PAM potentiation requires GluN2 LBD conformational flexibility. Together, these findings suggest that UBP684 and UBP753 stabilize the GluN2 LBD in an active conformation and thereby increase Po. Thus, UBP684 and UBP753 may serve as lead compounds for developing agents to enhance NMDAR activity in disorders associated with NMDAR hypofunction.
Bettini,
Identification and characterization of novel NMDA receptor antagonists selective for NR2A- over NR2B-containing receptors.
2010, Pubmed
Bettini,
Identification and characterization of novel NMDA receptor antagonists selective for NR2A- over NR2B-containing receptors.
2010,
Pubmed
Blanke,
Constitutive activation of the N-methyl-D-aspartate receptor via cleft-spanning disulfide bonds.
2008,
Pubmed
,
Xenbase
Bresink,
Effects of memantine on recombinant rat NMDA receptors expressed in HEK 293 cells.
1996,
Pubmed
Buller,
The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition.
1994,
Pubmed
,
Xenbase
Ceccon,
Distinct effect of pregnenolone sulfate on NMDA receptor subtypes.
2001,
Pubmed
Chesler,
Modulation of pH by neuronal activity.
1992,
Pubmed
Chopra,
Bidirectional Effect of Pregnenolone Sulfate on GluN1/GluN2A N-Methyl-D-Aspartate Receptor Gating Depending on Extracellular Calcium and Intracellular Milieu.
2015,
Pubmed
Clements,
Transmitter timecourse in the synaptic cleft: its role in central synaptic function.
1996,
Pubmed
Costa,
Structure-activity relationships for allosteric NMDA receptor inhibitors based on 2-naphthoic acid.
2012,
Pubmed
,
Xenbase
Costa,
A novel family of negative and positive allosteric modulators of NMDA receptors.
2010,
Pubmed
,
Xenbase
Coyle,
Glutamate and schizophrenia: beyond the dopamine hypothesis.
2006,
Pubmed
Diamond,
Transporters buffer synaptically released glutamate on a submillisecond time scale.
1997,
Pubmed
Dingledine,
The glutamate receptor ion channels.
1999,
Pubmed
Dravid,
Activation of recombinant NR1/NR2C NMDA receptors.
2008,
Pubmed
Eastwood,
Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons.
2005,
Pubmed
Greenwood,
Association analysis of 94 candidate genes and schizophrenia-related endophenotypes.
2012,
Pubmed
Hackos,
Diverse modes of NMDA receptor positive allosteric modulation: Mechanisms and consequences.
2017,
Pubmed
Hackos,
Positive Allosteric Modulators of GluN2A-Containing NMDARs with Distinct Modes of Action and Impacts on Circuit Function.
2016,
Pubmed
Halim,
Increased lactate levels and reduced pH in postmortem brains of schizophrenics: medication confounds.
2008,
Pubmed
Hardingham,
Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders.
2010,
Pubmed
Hollmann,
Zinc potentiates agonist-induced currents at certain splice variants of the NMDA receptor.
1993,
Pubmed
,
Xenbase
Horak,
Subtype-dependence of N-methyl-D-aspartate receptor modulation by pregnenolone sulfate.
2006,
Pubmed
Horak,
Molecular mechanism of pregnenolone sulfate action at NR1/NR2B receptors.
2004,
Pubmed
Ikeda,
Cloning and expression of the epsilon 4 subunit of the NMDA receptor channel.
1992,
Pubmed
,
Xenbase
Irvine,
Synthesis of a Series of Novel 3,9-Disubstituted Phenanthrenes as Analogues of Known NMDA Receptor Allosteric Modulators.
2015,
Pubmed
Irvine,
Coumarin-3-carboxylic acid derivatives as potentiators and inhibitors of recombinant and native N-methyl-D-aspartate receptors.
2012,
Pubmed
Ishii,
Molecular characterization of the family of the N-methyl-D-aspartate receptor subunits.
1993,
Pubmed
,
Xenbase
Jang,
A steroid modulatory domain on NR2B controls N-methyl-D-aspartate receptor proton sensitivity.
2004,
Pubmed
,
Xenbase
Kamat,
Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer's Disease: Understanding the Therapeutics Strategies.
2016,
Pubmed
Kantrowitz,
Thinking glutamatergically: changing concepts of schizophrenia based upon changing neurochemical models.
2010,
Pubmed
Khatri,
Structural determinants and mechanism of action of a GluN2C-selective NMDA receptor positive allosteric modulator.
2014,
Pubmed
,
Xenbase
Kostakis,
A steroid modulatory domain in NR2A collaborates with NR1 exon-5 to control NMDAR modulation by pregnenolone sulfate and protons.
2011,
Pubmed
,
Xenbase
Koutsilieri,
Excitotoxicity and new antiglutamatergic strategies in Parkinson's disease and Alzheimer's disease.
2007,
Pubmed
Kussius,
NMDA receptors with locked glutamate-binding clefts open with high efficacy.
2010,
Pubmed
Köhr,
NMDA receptor channels: subunit-specific potentiation by reducing agents.
1994,
Pubmed
Linsenbardt,
Different oxysterols have opposing actions at N-methyl-D-aspartate receptors.
2014,
Pubmed
,
Xenbase
Lipska,
Critical factors in gene expression in postmortem human brain: Focus on studies in schizophrenia.
2006,
Pubmed
Lisman,
Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia.
2008,
Pubmed
Low,
Molecular determinants of proton-sensitive N-methyl-D-aspartate receptor gating.
2003,
Pubmed
,
Xenbase
Luykx,
Genome-wide association study of NMDA receptor coagonists in human cerebrospinal fluid and plasma.
2015,
Pubmed
Malayev,
Inhibition of the NMDA response by pregnenolone sulphate reveals subtype selective modulation of NMDA receptors by sulphated steroids.
2002,
Pubmed
,
Xenbase
Mishina,
Molecular and functional diversity of the NMDA receptor channel.
1993,
Pubmed
Monaghan,
NR1 and NR2 subunit contributions to N-methyl-D-aspartate receptor channel blocker pharmacology.
1997,
Pubmed
,
Xenbase
Monaghan,
The excitatory amino acid receptors: their classes, pharmacology, and distinct properties in the function of the central nervous system.
1989,
Pubmed
Monyer,
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.
1994,
Pubmed
Mott,
Phenylethanolamines inhibit NMDA receptors by enhancing proton inhibition.
1998,
Pubmed
,
Xenbase
Mullasseril,
A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors.
2010,
Pubmed
Paoletti,
NMDA receptor subunits: function and pharmacology.
2007,
Pubmed
Paul,
The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-D-aspartate receptors.
2013,
Pubmed
Pivovarova,
Calcium-dependent mitochondrial function and dysfunction in neurons.
2010,
Pubmed
Prabakaran,
Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress.
2004,
Pubmed
Schizophrenia Working Group of the Psychiatric Genomics Consortium,
Biological insights from 108 schizophrenia-associated genetic loci.
2014,
Pubmed
Siesjö,
Acid-base homeostasis in the brain: physiology, chemistry, and neurochemical pathology.
1985,
Pubmed
Sugihara,
Structures and properties of seven isoforms of the NMDA receptor generated by alternative splicing.
1992,
Pubmed
,
Xenbase
Sullivan,
Identification of two cysteine residues that are required for redox modulation of the NMDA subtype of glutamate receptor.
1994,
Pubmed
,
Xenbase
Sun,
Schizophrenia gene networks and pathways and their applications for novel candidate gene selection.
2010,
Pubmed
Torrey,
Neurochemical markers for schizophrenia, bipolar disorder, and major depression in postmortem brains.
2005,
Pubmed
Traynelis,
Proton inhibition of N-methyl-D-aspartate receptors in cerebellar neurons.
1990,
Pubmed
Traynelis,
Control of proton sensitivity of the NMDA receptor by RNA splicing and polyamines.
1995,
Pubmed
,
Xenbase
Vicini,
Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors.
1998,
Pubmed
Watanabe,
Developmental changes in distribution of NMDA receptor channel subunit mRNAs.
1992,
Pubmed
Watanabe,
Distinct distributions of five N-methyl-D-aspartate receptor channel subunit mRNAs in the forebrain.
1993,
Pubmed
Watkins,
Excitatory amino acid transmitters.
1981,
Pubmed
Watkins,
Structure-activity relationships in the development of excitatory amino acid receptor agonists and competitive antagonists.
1990,
Pubmed
Wu,
Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor.
1991,
Pubmed