ArticleNeuropharmacology2012
Structure-activity relationships for allosteric NMDA receptor inhibitors based on 2-naphthoic acid.
Article in Neuropharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 34 citations in OpenAlex.
- NMDA Receptor Antagonists: Emerging Insights into Molecular Mechanisms and Clinical Applications in Neurological Disorders.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Calcium Modulating Effect of Polycyclic Cages: A Suitable Therapeutic Approach Against Excitotoxic-induced Neurodegeneration.Mini reviews in medicinal chemistry · 2024Review
- Positive and Negative Allosteric Modulators of N-Methyl-d-aspartate (NMDA) Receptors: Structure-Activity Relationships and Mechanisms of Action.Journal of medicinal chemistry · 2019Review
- Mechanism and properties of positive allosteric modulation of N-methyl-d-aspartate receptors by 6-alkyl 2-naphthoic acid derivatives.Neuropharmacology · 2017Article
- A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors.Scientific reports · 2017Article
- The Structure-Activity Relationship of a Tetrahydroisoquinoline Class of N-Methyl-d-Aspartate Receptor Modulators that Potentiates GluN2B-Containing N-Methyl-d-Aspartate Receptors.Journal of medicinal chemistry · 2017Article
- NMDA Receptors in the Central Nervous System.Methods in molecular biology (Clifton, N.J.) · 2017Article
- A novel class of negative allosteric modulators of NMDA receptor function.Bioorganic & medicinal chemistry letters · 2015Article
- Quantitative proteomics for cardiac biomarker discovery using isoproterenol-treated nonhuman primates.Journal of proteome research · 2014Article
- NMDA receptor modulators: an updated patent review (2013-2014).Expert opinion on therapeutic patents · 2014Review
- Structural determinants and mechanism of action of a GluN2C-selective NMDA receptor positive allosteric modulator.Molecular pharmacology · 2014Article
- Inhibition of GluN2A-containing N-methyl-D-aspartate receptors by 2-naphthoic acid.Molecular pharmacology · 2013Article
- Synthesis and structure activity relationship of tetrahydroisoquinoline-based potentiators of GluN2C and GluN2D containing N-methyl-D-aspartate receptors.Journal of medicinal chemistry · 2013Article
- Functional insights from glutamate receptor ion channel structures.Annual review of physiology · 2013Review
- 1,6-Di-bromo-naphthalen-2-ol methanol monosolvate.Acta crystallographica. Section E, Structure reports online · 2013Article
- Allosteric modulators for the treatment of schizophrenia: targeting glutamatergic networks.Current topics in medicinal chemistry · 2013Review
- Novel NMDA receptor modulators: an update.Expert opinion on therapeutic patents · 2012Review
- Pharmacological modulation of NMDA receptor activity and the advent of negative and positive allosteric modulators.Neurochemistry international · 2012Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
Abstract
Over-activation of N-methyl-d-aspartate (NMDA) receptors is critically involved in many neurological conditions, thus there has been considerable interest in developing NMDA receptor antagonists. We have recently identified a series of naphthoic and phenanthroic acid compounds that allosterically modulate NMDA receptors through a novel mechanism of action. In the present study, we have determined the structure-activity relationships of 18 naphthoic acid derivatives for the ability to inhibit the four GluN1/GluN2(A-D) NMDA receptor subtypes. 2-Naphthoic acid has low activity at GluN2A-containing receptors and yet lower activity at other NMDA receptors. 3-Amino addition, and especially 3-hydroxy addition, to 2-naphthoic acid increased inhibitory activity at GluN1/GluN2C and GluN1/GluN2D receptors. Further halogen and phenyl substitutions to 2-hydroxy-3-naphthoic acid leads to several relatively potent inhibitors, the most potent of which is UBP618 (1-bromo-2-hydroxy-6-phenylnaphthalene-3-carboxylic acid) with an IC(50) ∼ 2 μM at each of the NMDA receptor subtypes. While UBP618 is non-selective, elimination of the hydroxyl group in UBP618, as in UBP628 and UBP608, leads to an increase in GluN1/GluN2A selectivity. Of the compounds evaluated, specifically those with a 6-phenyl substitution were less able to fully inhibit GluN1/GluN2A, GluN1/GluN2B and GluN1/GluN2C responses (maximal % inhibition of 60-90%). Such antagonists may potentially have reduced adverse effects by not excessively blocking NMDA receptor signaling. Together, these studies reveal discrete structure-activity relationships for the allosteric antagonism of NMDA receptors that may facilitate the development of NMDA receptor modulator agents for a variety of neuropsychiatric and neurological conditions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.