Login / Signup

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

Julian A SchreiberDirk SchepmannBastian FrehlandSimone ThumMaia DatunashviliThomas BuddeMichael HollmannNathalie Strutz-SeebohmBernhard WünschGuiscard Seebohm
Published in: Communications biology (2019)
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.
Keyphrases
  • cell death
  • tissue engineering
  • cancer therapy
  • single molecule
  • cognitive decline
  • drug delivery
  • mass spectrometry
  • anti inflammatory
  • reactive oxygen species
  • drug induced
  • electronic health record
  • structural basis