Benzo[7]annulene-based GluN2B selective NMDA receptor antagonists: Surprising effect of a nitro group in 2-position

Bioorg Med Chem Lett. 2015 Dec 15;25(24):5748-51. doi: 10.1016/j.bmcl.2015.10.076. Epub 2015 Oct 31.

Abstract

Benzo[7]annulen-7-amines 7 without further polar substituents have been reported as conformationally restricted Ro 25-6981 analogs and show unexpectedly high GluN2B affinity. Herein the corresponding 2-NO2 derivatives 8 were synthesized and pharmacologically evaluated. NO2 derivatives 8 show 5- to 10-fold higher GluN2B affinity than the unsubstituted ligands 7. Docking studies of ligands 7c and 8c reveal an important contribution of the 2-NO2-substituent in determining the binding pose and modulating the GluN2B affinity.

Keywords: 2-Nitrobenzo[7]annulen-7-amines; Conformational restriction; Docking studies; GluN2B antagonists; NMDA receptor; Selectivity; Structure affinity relationships.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemical synthesis
  • Amines / chemistry*
  • Amines / metabolism
  • Binding Sites
  • Molecular Docking Simulation
  • Phenols / chemistry
  • Phenols / metabolism
  • Piperidines / chemistry
  • Piperidines / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Structure-Activity Relationship

Substances

  • Amines
  • Phenols
  • Piperidines
  • Receptors, N-Methyl-D-Aspartate
  • Ro 25-6981