1,1'-(propane-1,3-diyl)-bis(6,7-dimethoxyisoquinoline) | 755700-73-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 1,1'-(propane-1,3-diyl)-bis(6,7-dimethoxyisoquinoline)
• 英文别名: 6,7,6',7'-tetramethoxy-1,1'-propane-1,3-diyl-bis-isoquinoline；1,3-bis-(6,7-dimethoxy-[1]isoquinolyl)-propane；1,3-Bis-(6,7-dimethoxy-[1]isochinolyl)-propan；1,3-bis(6,7-dimethoxy-1-isoquinolyl)-propane；1-[3-(6,7-Dimethoxyisoquinolin-1-yl)propyl]-6,7-dimethoxyisoquinoline
• CAS: 755700-73-3
• 化学式: C₂₅H₂₆N₂O₄
• 分子量: 418.492
• InChiKey: PINOXMHMQPLDSD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  62.7
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1,1'-(propane-1,3-diyl)-bis(6,7-dimethoxyisoquinoline) 在 碘甲烷 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以97%的产率得到1,1'-(propane-1,3-diyl)-bis(6,7-dimethoxy-2-methylisoquinolinium) diiodide
  参考文献：
  名称：

  Bis-tetrahydroisoquinoline derivatives: AG525E1, a new step in the search for non-quaternary non-peptidic small conductance Ca2+-activated K+ channel blockers

  摘要：

  So far, small conductance Ca(2+)-activated K(+) channel (SK) blockers mostly consist of quaternary ammonium derivatives or peptides. Due to their physicochemical properties, these blockers are not suitable to study the physiological roles of SK channels in the central nervous system in vivo. Herein, we report the discovery of a chiral bis-tertiary amine with SK blocking properties from chemical modulation of laudanosine. AG525E1 has an affinity for SK channels (K(i) = 293 nM) approximately 100-fold higher than the tertiary compound laudanosine (K(i) similar to 30 mu M) and similar to the charged compound dequalinium (K(i) = 221 nM). AG525E1 equipotently blocks SK1, SK2 and SK3 currents in transfected cell lines. Because of its basic and lipophilic properties, it can reach central SK targets. (c) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2008.03.069
• 作为产物：
  描述：

  在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 生成 1,1'-(propane-1,3-diyl)-bis(6,7-dimethoxyisoquinoline)
  参考文献：
  名称：

  Synthesis and Radioligand Binding Studies of Bis-isoquinolinium Derivatives as Small Conductance Ca²⁺-Activated K⁺ Channel Blockers

  摘要：

  Starting from the scaffold of N-methyllaudanosine and N-methylnoscapine, which are known small conductance Ca2+-activated K+ channel blockers, original bis-isoquinolinium derivatives were synthezised and evaluated using binding studies, electrophysiology, and molecular modeling. These quaternary compounds are powerful blockers, and the most active ones have 10 times more affinity for the channels than dequalinium. The unsubstituted compounds possess a weaker affinity than the analogues having a 6,7-dimethoxy- or a 6,7,8-trimethoxy substitution. The length of the linker has no influence in the alkane derivatives. In relation to the xylene derivatives, the affinities are higher for the ortho and meta isomers. These results are well corroborated by a molecular modeling study. Finally, the most effective compounds have been tested in electrophysiological experiments on midbrain dopaminergic neurons and demonstrate the blocking potential of the apamin-sensitive after-hyperpolarization.

  DOI：

  10.1021/jm070412j

文献信息

• Synthesen von Verbindungen mit konstitutioneller Beziehung zum Emetin
  作者：M. Pailer、W. reifschneider

  DOI：10.1007/bf00900791

  日期：——
• Synthesis and Radioligand Binding Studies of Bis-isoquinolinium Derivatives as Small Conductance Ca²⁺-Activated K⁺ Channel Blockers
  作者：Amaury Graulich、Sébastien Dilly、Amaury Farce、Jacqueline Scuvée-Moreau、Olivier Waroux、Cédric Lamy、Philippe Chavatte、Vincent Seutin、Jean-François Liégeois

  DOI：10.1021/jm070412j

  日期：2007.10.1

  Starting from the scaffold of N-methyllaudanosine and N-methylnoscapine, which are known small conductance Ca2+-activated K+ channel blockers, original bis-isoquinolinium derivatives were synthezised and evaluated using binding studies, electrophysiology, and molecular modeling. These quaternary compounds are powerful blockers, and the most active ones have 10 times more affinity for the channels than dequalinium. The unsubstituted compounds possess a weaker affinity than the analogues having a 6,7-dimethoxy- or a 6,7,8-trimethoxy substitution. The length of the linker has no influence in the alkane derivatives. In relation to the xylene derivatives, the affinities are higher for the ortho and meta isomers. These results are well corroborated by a molecular modeling study. Finally, the most effective compounds have been tested in electrophysiological experiments on midbrain dopaminergic neurons and demonstrate the blocking potential of the apamin-sensitive after-hyperpolarization.
• Bis-tetrahydroisoquinoline derivatives: AG525E1, a new step in the search for non-quaternary non-peptidic small conductance Ca2+-activated K+ channel blockers
  作者：Amaury Graulich、Cédric Lamy、Livia Alleva、Sébastien Dilly、Philippe Chavatte、Johan Wouters、Vincent Seutin、Jean-François Liégeois

  DOI：10.1016/j.bmcl.2008.03.069

  日期：2008.6

  So far, small conductance Ca(2+)-activated K(+) channel (SK) blockers mostly consist of quaternary ammonium derivatives or peptides. Due to their physicochemical properties, these blockers are not suitable to study the physiological roles of SK channels in the central nervous system in vivo. Herein, we report the discovery of a chiral bis-tertiary amine with SK blocking properties from chemical modulation of laudanosine. AG525E1 has an affinity for SK channels (K(i) = 293 nM) approximately 100-fold higher than the tertiary compound laudanosine (K(i) similar to 30 mu M) and similar to the charged compound dequalinium (K(i) = 221 nM). AG525E1 equipotently blocks SK1, SK2 and SK3 currents in transfected cell lines. Because of its basic and lipophilic properties, it can reach central SK targets. (c) 2008 Elsevier Ltd. All rights reserved.