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

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

  • Eur J Med Chem. 2019 Feb 15:164:471-498. doi: 10.1016/j.ejmech.2018.12.054.
Mark W Irvine 1,  Guangyu Fang 1,  Kiran Sapkota 2,  Erica S Burnell 3,  Arturas Volianskis 4,  Blaise M Costa 5,  Georgia Culley 1,  Graham L Collingridge 6,  Daniel T Monaghan 2,  David E Jane 7
Affiliations

Affiliations

  • 1 Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, BS8 1TD, UK.
  • 2 Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5800, USA.
  • 3 Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, BS8 1TD, UK; School of Chemistry, National University of Ireland Galway, Galway, H91TK33, Ireland.
  • 4 Centre for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK; Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK.
  • 5 Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5800, USA; Pharmacology Division, Virginia College of Osteopathic Medicine, Blacksburg, VA, 24060, USA.
  • 6 Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada.
  • 7 Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, BS8 1TD, UK. Electronic address: david.jane@bristol.ac.uk.
PMID: 30622023 DOI: 10.1016/j.ejmech.2018.12.054
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.

Keywords

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

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