Quinazolin-4-one derivatives: A novel class of noncompetitive NR2C/D subunit-selective N-methyl-D-aspartate receptor antagonists
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Quinazolin-4-one derivatives : A novel class of noncompetitive NR2C/D subunit-selective N-methyl-D-aspartate receptor antagonists. / Mosley, Cara A; Acker, Timothy M; Hansen, Kasper Bø; Mullasseril, Praseeda; Andersen, Karen T; Le, Phuong; Vellano, Kimberly M; Bräuner-Osborne, Hans; Liotta, Dennis C; Traynelis, Stephen F.
I: Journal of Medicinal Chemistry, Bind 53, Nr. 15, 2010, s. 5476-5490.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Quinazolin-4-one derivatives
T2 - A novel class of noncompetitive NR2C/D subunit-selective N-methyl-D-aspartate receptor antagonists
AU - Mosley, Cara A
AU - Acker, Timothy M
AU - Hansen, Kasper Bø
AU - Mullasseril, Praseeda
AU - Andersen, Karen T
AU - Le, Phuong
AU - Vellano, Kimberly M
AU - Bräuner-Osborne, Hans
AU - Liotta, Dennis C
AU - Traynelis, Stephen F
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1021/jm100027p
DO - 10.1021/jm100027p
M3 - Journal article
C2 - 20684595
VL - 53
SP - 5476
EP - 5490
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 15
ER -
ID: 21695037