A common mechanism allows selective targeting of GluN2B subunit-containing N-methyl-D-aspartate receptors

Commun Biol. 2019 Nov 15;2:420. doi: 10.1038/s42003-019-0645-6. eCollection 2019.

Abstract

N-methyl-D-aspartate receptors (NMDARs), especially GluN2B-containing NMDARs, are associated with neurodegenerative diseases like Parkinson, Alzheimer and Huntington based on their high Ca2+ conductivity. Overactivation leads to high intracellular Ca2+ concentrations and cell death rendering GluN2B-selective inhibitors as promising drug candidates. Ifenprodil represents the first highly potent prototypical, subtype-selective inhibitor of GluN2B-containing NMDARs. However, activity of ifenprodil on serotonergic, adrenergic and sigma receptors limits its therapeutic use. Structural reorganization of the ifenprodil scaffold to obtain 3-benzazepines retained inhibitory GluN2B activity but decreased the affinity at the mentioned non-NMDARs. While scaffold optimization improves the selectivity, the molecular inhibitory mechanism of these compounds is still not known. Here, we show a common inhibitory mechanism of ifenprodil and the related 3-benzazepines by mutational modifications of the receptor binding site, chemical modifications of the 3-benzazepine scaffold and subsequent in silico simulation of the inhibitory mechanism.

Keywords: Ligand-gated ion channels; Receptor pharmacology; Structural biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzazepines / chemistry
  • Benzazepines / pharmacology
  • Binding Sites
  • Dose-Response Relationship, Drug
  • Drug Discovery* / methods
  • Humans
  • Hydrogen Bonding
  • Ligands
  • Models, Molecular*
  • Molecular Conformation
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Protein Binding
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / chemistry*
  • Structure-Activity Relationship

Substances

  • Benzazepines
  • Ligands
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate

Associated data

  • figshare/10.6084/m9.figshare.9751739.v1
  • figshare/10.6084/m9.figshare.9751751.v1
  • figshare/10.6084/m9.figshare.9751742.v1
  • figshare/10.6084/m9.figshare.9751745.v1
  • figshare/10.6084/m9.figshare.9751748.v1
  • figshare/10.6084/m9.figshare.9751736.v1