Enantiomeric propanolamines as selective N-methyl-D-aspartate 2B receptor antagonists.
Enantiomeric propanolamines as selective N-methyl-D-aspartate 2B receptor antagonists.
复制标题
对映体丙醇胺作为选择性 N-甲基-D-天冬氨酸 2B 受体拮抗剂。
DOI：
10.1021/jm8002153
复制
发表时间：
2008
影响因子：
7.3
通讯作者：
Dingledi
中科院分区：
文献类型：
--
作者：
Tahirovic,YesimA;Geballe,Matthew;Gruszecka-Kowalik,Ewa;Myers,ScottJ;Lyuboslavsky,Polina;Le,Phuong;French,Adam;Irier,Hasan;Choi,Woo-Baeg;Easterling,Keith;Yuan,Hongjie;Wilson,LawrenceJ;Kotloski,Robert;McNamara,JamesO;Dingledi
对映体丙醇胺是一类新型的NR2B选择性NMDA受体拮抗剂。最有效的试剂是联芳基结构，经过六步合成，总收率在11−%之间。这些化合物是含有NR2B的重组N-甲基-D-天冬氨酸受体的有效和选择性的抑制剂，其IC50值在30−100 nM之间。效价受两个环上的取代和中心位置的胺氮的强烈控制。SAR分析表明，平衡的极性和链长因子提供了最大的抑制效力。基于三维形状分析和静电互补的结构比较支持这一结论。这些拮抗剂在体外和体内的缺血细胞死亡模型中都具有神经保护作用。此外，一些化合物还显示出抗惊厥的特性。与上一代NMDA受体拮抗剂和一些NR2B选择性拮抗剂不同，本系列丙醇胺不会导致啮齿动物运动增加。因此，NR2B选择性拮抗剂表现出一系列有趣的治疗特性。
Enantiomeric propanolamines have been identified as a new class of NR2B-selective NMDA receptor antagonists. The most effective agents are biaryl structures, synthesized in six steps with overall yields ranging from 11−64%. The compounds are potent and selective inhibitors of NR2B-containing recombinant NMDA receptors with IC50values between 30−100 nM. Potency is strongly controlled by substitution on both rings and the centrally located amine nitrogen. SAR analysis suggests that well-balanced polarity and chain-length factors provide the greatest inhibitory potency. Structural comparisons based on 3D shape analysis and electrostatic complementarity support this conclusion. The antagonists are neuroprotective in both in vitro and in vivo models of ischemic cell death. In addition, some compounds exhibit anticonvulsant properties. Unlike earlier generation NMDA receptor antagonists and some NR2B-selective antagonists, the present series of propanolamines does not cause increased locomotion in rodents. Thus, the NR2B-selective antagonists exhibit a range of therapeutically interesting properties.