Synthesis, structural activity-relationships, and biological evaluation of novel amide-based allosteric binding site antagonists in NR1A/NR2B N-methyl-D-aspartate receptors.
Synthesis, structural activity-relationships, and biological evaluation of novel amide-based allosteric binding site antagonists in NR1A/NR2B N-methyl-D-aspartate receptors.
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DOI：
10.1016/j.bmc.2009.05.085
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发表时间：
2009-09-01
影响因子：
3.5
通讯作者：
Liotta, Dennis C.
中科院分区：
文献类型：
--
作者：
Mosley, Cara A.;Myers, Scott J.;Murray, Ernest E.;Santangelo, Rose;Tahirovic, Yesim A.;Kurtkaya, Natalie;Mullasseril, Praseeda;Yuan, Hongjie;Lyuboslavsky, Polina;Le, Phuong;Wilson, Lawrence J.;Yepes, Manuel;Dingledine, Ray;Traynelis, Stephen F.;Liotta, Dennis C.
合成了一类新型酰胺类联芳基NR 2B选择性NMDA受体拮抗剂，并对其构效关系进行了分析。一些研究的化合物是含NR 2B的NMDA受体的有效的、选择性的、非竞争性的和电压非依赖性的拮抗剂。与这类拮抗剂的创始成员（艾芬地尔）一样，该系列的几种感兴趣的化合物与NR 2B亚基的氨基末端结构域结合以抑制功能。抗肿瘤效力受连接体长度、柔性和氢键结合机会的调节。然而，与先前描述的在多种单胺受体上表现出脱靶活性的NR 2B选择性NMDA拮抗剂类别不同，本文所述的化合物显示出对hERG通道和α1-肾上腺素能受体的显著减弱的作用。所讨论的化合物的选择在体内具有可接受的半衰期，并且预测渗透血脑屏障。这些数据一起表明，掩蔽NR 2B选择性拮抗剂的接头区域上的带电原子可以减少不期望的副作用，同时仍然保持靶向效力。
The synthesis and structure–activity relationship analysis of a novel class of amide-based biaryl NR2B-selective NMDA receptor antagonists are presented. Some of the studied compounds are potent, selective, non-competitive, and voltage-independent antagonists of NR2B-containing NMDA receptors. Like the founding member of this class of antagonists (ifenprodil), several interesting compounds of the series bind to the amino terminal domain of the NR2B subunit to inhibit function. Analogue potency is modu-lated by linker length, flexibility, and hydrogen bonding opportunities. However, unlike previously described classes of NR2B-selective NMDA antagonists that exhibit off-target activity at a variety of monoamine receptors, the compounds described herein show much diminished effects against the hERG channel and α1-adrenergic receptors. Selections of the compounds discussed have acceptable half-lives in vivo and are predicted to permeate the blood–brain barrier. These data together suggest that masking charged atoms on the linker region of NR2B-selective antagonists can decrease undesirable side effects while still maintaining on-target potency.
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影响因子：
2.5
作者：
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通讯作者：
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影响因子：
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