1-(3',4'-dimethoxybenzyl)-2-methylisoquinolinium iodide | 50370-93-9

• 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-(3',4'-dimethoxybenzyl)-2-methylisoquinolinium iodide
• 英文别名: 1-[(3,4-dimethoxyphenyl)methyl]-2-methylisoquinolin-2-ium;iodide
• CAS: 50370-93-9
• 化学式: C₁₉H₂₀NO₂*I
• 分子量: 421.278
• InChiKey: MUSYLBYXFURACS-UHFFFAOYSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  0.28
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  22.3
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(3',4'-dimethoxybenzyl)-2-methylisoquinolinium iodide 以80%的产率得到
  参考文献：
  名称：

  GINOS J. Z., J. ORG. CHEM. , 1975, 40, NO 9, 1191-1195

  摘要：

  DOI：
• 作为产物：
  描述：

  1-(3',4'-dimethoxybenzyl)isoquinoline 、 碘甲烷 反应 4.0h， 以503 mg的产率得到1-(3',4'-dimethoxybenzyl)-2-methylisoquinolinium iodide
  参考文献：
  名称：

  Dopamine Transporter and Catechol-O-methyltransferase Activities Are Required for the Toxicity of 1-(3‘,4‘-Dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline

  摘要：

  1-(3',4'-Dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline [3',4'DHBnTIQ (1)] is an endogenous parkinsonism-inducing substance. It is taken up into dopaminergic neurons via the dopamine transporter, inhibits mitochondrial respiration, and induces parkinsonism in mice. We synthesized four derivatives [aromatized, N-methylated, N-methyl-aromatized, and O-methylated (2-5, respectively)] and studied the cellular uptake and cytotoxicity of 1-5, as well as the metabolism of 1. All except the O-methyl derivative (5) were specifically taken up by the dopamine transporter, but 1 was taken up most efficiently. Relative to 1, oxidation reduced upsilon (max), N-methylation markedly increased K-m, and O-methylation eliminated the uptake activity. The cytotoxicity of 1-5 was examined in a mesencephalic cell. primary culture. Compound I reduced cell viability by nearly 80% at 100 muM, but the other compounds had little or no effect on cell viability. In vivo and in vitro studies revealed that I was O-methylated by soluble catechol-O-methyltransferase (COMT). Aromatization and N-methylation of 1 were not observed. We found that dopamine transporter inhibitors and a COMT inhibitor each blocked the cytotoxicity of I, indicating that uptake and O-methylation are both necessary for neurotoxicity. Thus, we consider that 1 is taken up into dopaminergic neurons via the dopamine transporter and then converted by COMT to 5, which has cytotoxic and parkinsonism-inducing activities.

  DOI：

  10.1021/tx000047y

文献信息

• Synthesis and biological evaluation of N-methyl-laudanosine iodide analogues as potential SK channel blockers
  作者：A. Graulich、F. Mercier、J. Scuvée-Moreau、V. Seutin、J.-F. Liégeois

  DOI：10.1016/j.bmc.2004.11.025

  日期：2005.2

  Neuronal action potentials are followed by an afterhyperpolarisation (AHP), which is mediated by small conductance Ca2+-activated K+ channels (SK channels or KCa2 channels). This AHP plays an important role in regulating neuronal activity and agents modulating AHP amplitude could have a potential therapeutic interest. It was previously shown that N-methyl-bicuculline iodide blocks SK channels but its GABA(A) activity represents a serious drawback. In view of the structural analogy between bicuculline and laudanosine 14, several N-quaternary analogues of the latter were developed. It was shown that N-methyl-laudanosine 15 (NML) and N-ethyl-laudanosine 16 induce a reversible and relatively specific blockade of the apamin sensitive AHP in dopaminergic neurones with mean IC(50)s of 15, and 47 muM, respectively. Laudanosine 14, N-butyl-17 and N-benzyl-18 derivatives were less potent. In order to find pharmacophore elements, modifications were performed at different positions such as C-1, C-6 and C-7. Intracellular recordings on rat midbrain dopaminergic neurones were made in order to evaluate the putative blockade of SK channels by these molecules. Simplified structures such as tetrahydroisoquinoline derivatives with H or Me at C-I 1-6 presented no significant activity at 300 muM. The presence of a 1-(3,4-dimethoxybenzy]) moiety seems an important feature. Indeed, compound 8 showed a blockade of the AHP of only 33% at 300 muM while compound 13 blocked it by 67%, respectively, at the same concentration. Binding experiments were also performed. Binding affinities for SK channels are in good agreement with electrophysiological data. These results indicate that the presence of a charged nitrogen group is an essential point for the affinity on SK channels. Finally, because of the similar activity of both enantionters of NML 19 and 20, the interaction site may present a symmetrical configuration. (C) 2004 Elsevier Ltd. All rights reserved.