title: Quinazolin-4-one derivatives: A novel class of noncompetitive NR2C/D subunit-selective N-methyl-D-aspartate receptor antagonists.
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.
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia 30033, USA.
authors.forename: Cara A
authors.initials: CA
authors.lastname: Mosley
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Acker
authors.forename: Kasper B
authors.initials: KB
authors.lastname: Hansen
authors.forename: Praseeda
authors.initials: P
authors.lastname: Mullasseril
authors.forename: Karen T
authors.initials: KT
authors.lastname: Andersen
authors.forename: Phuong
authors.initials: P
authors.lastname: Le
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Vellano
authors.forename: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
mesh_terms: D000818:Animals; D001665:Binding Sites; D005260:Female; D008958:Models, Molecular; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000502:physiology; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: C432823:NR2C NMDA receptor; C464436:NR2D NMDA receptor; D021122:Protein Subunits; D052999:Quinazolinones; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins