(+/-)-N-ethyl-Laudanosine iodide | 23669-24-1

• 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: (+/-)-N-ethyl-Laudanosine iodide
• 英文别名: laudanosine ethyl iodide；2-ethyl-6,7-dimethoxy-2-methyl-1-veratryl-1,2,3,4-tetrahydro-isoquinolinium; iodide；2-Aethyl-6,7-dimethoxy-2-methyl-1-veratryl-1,2,3,4-tetrahydro-isochinolinium; Jodid；1-[(3,4-dimethoxyphenyl)methyl]-2-ethyl-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-2-ium;iodide
• CAS: 23669-24-1
• 化学式: C₂₃H₃₂NO₄*I
• 分子量: 513.416
• InChiKey: HZISVVFLIYMDBO-UHFFFAOYSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  1.03
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  36.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  (S)-劳丹素 在 乙醇 作用下， 生成 (+/-)-N-ethyl-Laudanosine iodide
  参考文献：
  名称：

  Pictet; Athanasescu, Chemische Berichte, 1900, vol. 33, p. 2350

  摘要：

  DOI：

文献信息

• Methyl-Laudanosine: A New Pharmacological Tool to Investigate the Function of Small-Conductance Ca²⁺-Activated K⁺Channels
  作者：Jacqueline Scuvee-Moreau、Jean-François Liegeois、Laurent Massotte、Vincent Seutin

  DOI：10.1124/jpet.302.3.1176

  日期：2002.9.1

  Small-conductance Ca2+-activated K+ channels (SK channels) underlie the prolonged postspike afterhyperpolarization (AHP) observed in many central neurons and play an important role in modulating neuronal activity. However, a lack of specific and reversible blockers of these channels hampers their study in various experimental conditions. Because previous work has shown that bicuculline salts block these channels, we examined whether related alkaloids, namely laudanosine quaternary derivatives, would produce similar effects. Intracellular recordings were performed on rat midbrain dopaminergic neurons and hippocampus CA1 pyramidal cells. Binding experiments were performed on rat cerebral cortex membranes. Laudanosine, methyl-laudanosine, and ethyl-laudanosine blocked the apamin-sensitive AHP of dopaminergic neurons with mean IC50 values of 152, 15, and 47 μM, respectively. The benzyl and butyl derivatives were less potent. Methyl-laudanosine had no effect on the Ih current, action potential parameters, or membrane resistance of dopaminergic cells, or on the decrease in input resistance induced by muscimol, indicating a lack of antagonism at GABAA receptors. Interestingly, 100 μM methyl-laudanosine induced a significant increase in spiking frequency of dopaminergic neurons but not of CA1 pyramidal cells, suggesting the possibility of regional selectivity. Binding experiments on laudanosine derivatives were in good agreement with electrophysiological data. Moreover, methyl-laudanosine has no affinity for voltage-gated potassium channels, and its affinity for SK channels (IC504 μM) is superior to its affinity for muscarinic (IC50114 μM) and neuronal nicotinic (IC50 ≥367 μM) receptors . Methyl-laudanosine may be a valuable pharmacological tool to investigate the role of SK channels in various experimental models.

  小传导 Ca2+ 激活 K+ 通道（SK 通道）是在许多中枢神经元中观察到的尖峰后超极化（AHP）延长的基础，在调节神经元活动中发挥着重要作用。然而，这些通道缺乏特异性和可逆性的阻断剂，阻碍了在各种实验条件下对它们的研究。由于之前的研究表明双丘氨酸盐类能阻断这些通道，我们研究了相关生物碱（即月桂苷四元衍生物）是否会产生类似的效果。我们在大鼠中脑多巴胺能神经元和海马 CA1 锥体细胞上进行了细胞内记录。在大鼠大脑皮层膜上进行了结合实验。鸦胆子碱、甲基鸦胆子碱和乙基鸦胆子碱阻断了多巴胺能神经元对阿帕明敏感的AHP，其平均IC50值分别为152、15和47 μM。苄基和丁基衍生物的效力较弱。甲基-月桂苷对多巴胺能细胞的 Ih 电流、动作电位参数或膜电阻，或对 muscimol 引起的输入电阻下降没有影响，这表明它对 GABAA 受体缺乏拮抗作用。有趣的是，100 μM 甲基-月桂苷能显著增加多巴胺能神经元的尖峰频率，但不能增加 CA1 锥体细胞的尖峰频率，这表明可能存在区域选择性。月桂苷衍生物的结合实验与电生理数据十分吻合。此外，甲基-月桂苷对电压门控钾通道没有亲和力，而它对 SK 通道的亲和力（IC504 μM）优于它对毒蕈碱受体（IC50114 μM）和神经元烟碱受体（IC50 ≥367 μM）的亲和力。甲基-鸦片甙可能是研究 SK 通道在各种实验模型中作用的一种有价值的药理学工具。
• 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.
• Pictet; Athanasescu, Chemische Berichte, 1900, vol. 33, p. 2350
  作者：Pictet、Athanasescu

  DOI：——

  日期：——