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

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)471-498
Number of pages28
JournalEuropean Journal of Medicinal Chemistry
Volume164
Early online date28 Dec 2018
DOIs
DateAccepted/In press - 22 Dec 2018
DateE-pub ahead of print - 28 Dec 2018
DatePublished (current) - 15 Feb 2019

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.

    Research areas

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

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  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Elsevier at https://www.sciencedirect.com/science/article/pii/S0223523418310973 . Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 1 MB, PDF document

    Embargo ends: 28/12/19

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    Licence: CC BY-NC-ND

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