Department of Chemistry, Emory University, Atlanta, Georgia 30033, USA.
J Med Chem. 2010 Aug 12;53(15):5476-90. doi: 10.1021/jm100027p.
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.
我们描述了一类新的亚单位选择性 N-甲基-D-天冬氨酸（NMDA）选择性离子型谷氨酸受体拮抗剂，其包含（E）-3-苯基-2-苯乙烯基喹唑啉-4（3H）-酮骨架。这些喹唑啉-4-酮衍生物对重组 NMDA 受体功能的抑制是非竞争性和电压依赖性的，这表明该类化合物不会对受体的激动剂结合位点发挥作用或阻断通道孔。本文所述的化合物类似于 CP-465,022（（S）-3-（2-氯苯基）-2- [2-（6-二乙基氨基甲基-吡啶-2-基）-乙烯基]-6-氟-3H-喹唑啉-4-酮），是 AMPA 选择性谷氨酸受体的非竞争性拮抗剂。然而，环取代基的修饰导致了对重组 NMDA 受体的选择性大于 100 倍的类似物，超过了 AMPA 和海人藻酸受体。此外，在该系列化合物中，鉴定出对包含 NR2C/D 的重组受体具有 50 倍选择性的类似物，超过了包含 NR2A/B 的受体。这些化合物代表了一类新的非竞争性亚单位选择性 NMDA 受体拮抗剂。
