Quinazolin-4-one Derivatives: A Novel Class of Noncompetitive NR2C/D Subunit-selective N-methyl-D-aspartate Receptor Antagonists

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2010 Aug 6

PMID 20684595

Citations 44

Authors

Cara A Mosley

Timothy M Acker

Kasper B Hansen

Praseeda Mullasseril

Karen T Andersen

Phuong Le

Kimberly M Vellano

Hans Brauner-Osborne

Dennis C Liotta

Stephen F Traynelis

Affiliations

Soon will be listed here.

Abstract

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.

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