Investigation of the structural requirements for N-methyl-D-aspartate receptor positive and negative allosteric modulators based on 2-naphthoic acid

Mark W. Irvine, Guangyu Fang, Kiran Sapkota, Erica S. Burnell, Arturas Volianskis, Blaise M. Costa, Georgia Culley, Graham L. Collingridge, Daniel T Monaghan, David E. Jane

Research output: Contribution to journalArticle

Abstract

The N-methyl-D-aspartate receptor (NMDAR), a ligand-gated ion channel activated by L-glutamate and glycine, plays a major role in the synaptic plasticity underlying learning and memory. NMDARs are involved in neurodegenerative disorders such as Alzheimer's and Parkinson's disease and NMDAR hypofunction is implicated in schizophrenia. Herein we describe structure-activity relationship (SAR) studies on 2-naphthoic acid derivatives to investigate structural requirements for positive and negative allosteric modulation of NMDARs. These studies identified compounds such as UBP684 (14b), which act as pan potentiators by enhancing NMDAR currents in diheteromeric NMDAR tetramers containing GluN1 and GluN2A-D subunits. 14b and derivatives thereof are useful tools to study synaptic function and have potential as leads for the development of drugs to treat schizophrenia and disorders that lead to a loss of cognitive function. In addition, SAR studies have identified a series of styryl substituted compounds with partial NAM activity and a preference for inhibition of GluN2D versus the other GluN2 subunits. In particular, the 3-and 2-nitrostyryl derivatives UBP783 (79i) and UBP792 (79h) had IC50s of 1.4 μM and 2.9 μM, respectively, for inhibition of GluN2D but showed only 70–80% maximal inhibition. GluN2D has been shown to play a role in excessive pain transmission due to nerve injury and potentially in neurodegenerative disorders. Partial GluN2D inhibitors may be leads for the development of drugs to treat these disorders without the adverse effects observed with full NMDAR antagonists.

Original languageEnglish (US)
Pages (from-to)471-498
Number of pages28
JournalEuropean Journal of Medicinal Chemistry
Volume164
DOIs
StatePublished - Feb 15 2019

Fingerprint

N-Methyl-D-Aspartate Receptors
Modulators
Structure-Activity Relationship
Derivatives
Neurodegenerative Diseases
Schizophrenia
Ligand-Gated Ion Channels
Neuronal Plasticity
Pharmaceutical Preparations
Glycine
Cognition
Plasticity
Parkinson Disease
Glutamic Acid
Alzheimer Disease
Modulation
2-naphthoic acid
Learning
Data storage equipment
Pain

Keywords

  • 2-Naphthoic acid
  • GluN2
  • N-Methyl-D-aspartate receptor
  • NMDA
  • Negative allosteric modulator
  • Positive allosteric modulator

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Investigation of the structural requirements for N-methyl-D-aspartate receptor positive and negative allosteric modulators based on 2-naphthoic acid. / Irvine, Mark W.; Fang, Guangyu; Sapkota, Kiran; Burnell, Erica S.; Volianskis, Arturas; Costa, Blaise M.; Culley, Georgia; Collingridge, Graham L.; Monaghan, Daniel T; Jane, David E.

In: European Journal of Medicinal Chemistry, Vol. 164, 15.02.2019, p. 471-498.

Research output: Contribution to journalArticle

Irvine, Mark W. ; Fang, Guangyu ; Sapkota, Kiran ; Burnell, Erica S. ; Volianskis, Arturas ; Costa, Blaise M. ; Culley, Georgia ; Collingridge, Graham L. ; Monaghan, Daniel T ; Jane, David E. / Investigation of the structural requirements for N-methyl-D-aspartate receptor positive and negative allosteric modulators based on 2-naphthoic acid. In: European Journal of Medicinal Chemistry. 2019 ; Vol. 164. pp. 471-498.
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AU - Volianskis, Arturas

AU - Costa, Blaise M.

AU - Culley, Georgia

AU - Collingridge, Graham L.

AU - Monaghan, Daniel T

AU - Jane, David E.

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