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 journalArticlepeer-review

28 Scopus citations

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 2012

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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