2-{4-[4-(6-nitroquinolin-2-yl)piperazin-1-yl]butyl}isoindole-1,3-dione | 1363634-36-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 2-{4-[4-(6-nitroquinolin-2-yl)piperazin-1-yl]butyl}isoindole-1,3-dione
• 英文别名: 2-[4-[4-(6-Nitroquinolin-2-yl)piperazin-1-yl]butyl]isoindole-1,3-dione
• CAS: 1363634-36-9
• 化学式: C₂₅H₂₅N₅O₄
• 分子量: 459.505
• InChiKey: PRTVRLZORAJMAP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  103
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  邻苯二甲酸亚胺 在 18-冠醚-6 、 potassium carbonate 作用下， 以 甲苯 为溶剂， 反应 144.0h， 生成 2-{4-[4-(6-nitroquinolin-2-yl)piperazin-1-yl]butyl}isoindole-1,3-dione
  参考文献：
  名称：

  Synthesis, in vitro binding studies and docking of long-chain arylpiperazine nitroquipazine analogues, as potential serotonin transporter inhibitors

  摘要：

  It is well known that 6-nitroquipazine exhibits about 150-fold higher affinity for the serotonin transporter (SERT) than quipazine and recently we showed quipazine buspirone analogues with high to moderate SERT affinity. Now we have designed and synthesized several 6-nitroquipazine buspirone derivatives. Unexpectedly, their SERT binding affinities were moderate, and much lower than that of the previously studied quipazine buspirone analogues. To explain these findings, docking studies of both groups of compounds into two different homology models of human SERT was performed using a flexible target-ligand docking approach (4D docking). The crystal structures of leucine transporter from Aquilex aeolicus in complex with leucine and with tryptophan were used as templates for the SERT models in closed and outward-facing conformations, respectively. We found that the latter conformation represents the most reliable model for binding of buspirone analogues. Docking into that model showed that the nitrated compounds acquire a rod like shape in the binding pocket with polar groups (nitro- and imido-) at the ends of the rod. 6-Nitro substituents gave steric clashes with amino acids located at the extracellular loop 4, which may explain their lower affinity than corresponding quipazine buspirone analogues. The results from the present study may suggest chemical design strategies to improve the SERT modulators. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.01.012

文献信息

• Synthesis, in vitro binding studies and docking of long-chain arylpiperazine nitroquipazine analogues, as potential serotonin transporter inhibitors
  作者：Małgorzata Jarończyk、Karol Wołosewicz、Mari Gabrielsen、Gabriel Nowak、Irina Kufareva、Aleksander P. Mazurek、Aina W. Ravna、Ruben Abagyan、Andrzej J. Bojarski、Ingebrigt Sylte、Zdzisław Chilmonczyk

  DOI：10.1016/j.ejmech.2012.01.012

  日期：2012.3

  It is well known that 6-nitroquipazine exhibits about 150-fold higher affinity for the serotonin transporter (SERT) than quipazine and recently we showed quipazine buspirone analogues with high to moderate SERT affinity. Now we have designed and synthesized several 6-nitroquipazine buspirone derivatives. Unexpectedly, their SERT binding affinities were moderate, and much lower than that of the previously studied quipazine buspirone analogues. To explain these findings, docking studies of both groups of compounds into two different homology models of human SERT was performed using a flexible target-ligand docking approach (4D docking). The crystal structures of leucine transporter from Aquilex aeolicus in complex with leucine and with tryptophan were used as templates for the SERT models in closed and outward-facing conformations, respectively. We found that the latter conformation represents the most reliable model for binding of buspirone analogues. Docking into that model showed that the nitrated compounds acquire a rod like shape in the binding pocket with polar groups (nitro- and imido-) at the ends of the rod. 6-Nitro substituents gave steric clashes with amino acids located at the extracellular loop 4, which may explain their lower affinity than corresponding quipazine buspirone analogues. The results from the present study may suggest chemical design strategies to improve the SERT modulators. (C) 2012 Elsevier Masson SAS. All rights reserved.