Structure-activity relationships for allosteric NMDA receptor inhibitors based on 2-naphthoic acid

Blaise Mathias Costa, Mark W. Irvine, Guangyu Fang, Richard J. Eaves, Maria Belen Mayo-Martin, Bodo Laube, David E. Jane, Daniel T Monaghan

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1730-1736
Number of pages7
JournalNeuropharmacology
Volume62
Issue number4
DOIs
StatePublished - Mar 1 2012

Fingerprint

Structure-Activity Relationship
Halogens
aspartic acid receptor
2-naphthoic acid
Carboxylic Acids
N-Methyl-D-Aspartate Receptors
Hydroxyl Radical

Keywords

  • Allosteric modulator
  • Antagonist
  • Glutamate
  • NMDA receptors
  • Oocyte

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Structure-activity relationships for allosteric NMDA receptor inhibitors based on 2-naphthoic acid. / Costa, Blaise Mathias; Irvine, Mark W.; Fang, Guangyu; Eaves, Richard J.; Mayo-Martin, Maria Belen; Laube, Bodo; Jane, David E.; Monaghan, Daniel T.

In: Neuropharmacology, Vol. 62, No. 4, 01.03.2012, p. 1730-1736.

Research output: Contribution to journalArticle

Costa, BM, Irvine, MW, Fang, G, Eaves, RJ, Mayo-Martin, MB, Laube, B, Jane, DE & Monaghan, DT 2012, 'Structure-activity relationships for allosteric NMDA receptor inhibitors based on 2-naphthoic acid', Neuropharmacology, vol. 62, no. 4, pp. 1730-1736. https://doi.org/10.1016/j.neuropharm.2011.11.019
Costa, Blaise Mathias ; Irvine, Mark W. ; Fang, Guangyu ; Eaves, Richard J. ; Mayo-Martin, Maria Belen ; Laube, Bodo ; Jane, David E. ; Monaghan, Daniel T. / Structure-activity relationships for allosteric NMDA receptor inhibitors based on 2-naphthoic acid. In: Neuropharmacology. 2012 ; Vol. 62, No. 4. pp. 1730-1736.
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