Quinazolin-4-one derivatives: A novel class of noncompetitive NR2C/D subunit-selective N-methyl-D-aspartate receptor antagonists

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Cara A Mosley
  • Timothy M Acker
  • Kasper Bø Hansen
  • Praseeda Mullasseril
  • Karen T Andersen
  • Phuong Le
  • Kimberly M Vellano
  • Bräuner-Osborne, Hans
  • Dennis C Liotta
  • Stephen F Traynelis
We describe a new class of subunit-selective antagonists of N-methyl D-aspartate (NMDA)-selective ionotropic glutamate receptors that contain the (E)-3-phenyl-2-styrylquinazolin-4(3H)-one backbone. The inhibition of recombinant NMDA receptor function induced by these quinazolin-4-one derivatives is noncompetitive and voltage-independent, suggesting that this family of compounds does not exert action on the agonist binding site of the receptor or block the channel pore. The compounds described here resemble CP-465,022 ((S)-3-(2-chlorophenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one), a noncompetitive antagonist of AMPA-selective glutamate receptors. However, modification of ring substituents resulted in analogues with greater than 100-fold selectivity for recombinant NMDA receptors over AMPA and kainate receptors. Furthermore, within this series of compounds, analogues were identified with 50-fold selectivity for recombinant NR2C/D-containing receptors over NR2A/B containing receptors. These compounds represent a new class of noncompetitive subunit-selective NMDA receptor antagonists.
TidsskriftJournal of Medicinal Chemistry
Udgave nummer15
Sider (fra-til)5476-5490
StatusUdgivet - 2010

ID: 21695037