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Author Notes:

Corresponding Author for Chemistry Department of Chemistry, Emory University, 1515 Dickey Drive 30033 Atlanta, GA. Tel 404 727 6602 Fax 404 412 8649 dliotta@emory.edu


Research Funding:

This work was supported by the Michael J. Fox Foundation (SFT), the Alfred Benzon Foundation (KBH), the Villum Kann Rasmussen Foundation (KBH), the Lundbeck Foundation (KBH), the NIH (NS065371, NS036654 ST), Pharmacological Sciences Training grant (T32 GM008602, TA), and a research grant from Pfizer (ST).

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


Journal Title:

Journal of Medicinal Chemistry


Volume 53, Number 15


, Pages 5476-5490

Type of Work:

Article | Post-print: After Peer Review


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 non-competitive 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 non-competitive 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 non-competitive subunit-selective NMDA receptor antagonists.

Copyright information:

© 2010 American Chemical Society

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