NS8593盐酸盐 | 875755-24-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 中文名称: NS8593盐酸盐
• 中文别名: N-[(1R)-1,2,3,4-四氢-1-萘]-1H-苯并咪唑-2-胺盐酸盐
• 英文名称: NS 8593 hydrochloride
• 英文别名: NS8593；N-[(1R)-1,2,3,4-Tetrahydro-1-naphthalenyl]-1H-Benzimidazol-2-amine hydrochloride；N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-benzimidazol-2-amine;hydrochloride
• CAS: 875755-24-1
• 化学式: C₁₇H₁₇N₃*ClH
• 分子量: 299.803
• InChiKey: VWEKCDTXUUPBNA-PFEQFJNWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.47
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  40.7
• 氢给体数：
  3
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  2-氯苯并咪唑 、 (R)-(-)-1,2,3,4-四氢-1-萘胺 以 乙腈 为溶剂， 反应 0.67h， 以65%的产率得到NS8593盐酸盐
  参考文献：
  名称：

  Inhibitory Gating Modulation of Small Conductance Ca²⁺-Activated K⁺Channels by the Synthetic Compound (R)-N-(Benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphtylamine (NS8593) Reduces Afterhyperpolarizing Current in Hippocampal CA1 Neurons

  摘要：

  SK 通道是小电导 Ca2+ 激活的 K+ 通道，对控制神经元兴奋性、微调发射模式和调节突触机制非常重要。经典的 SK 通道药理学主要集中在多肽阿帕明（apamin）上，它通过孔阻断机制在细胞外发挥作用。1-乙基-2-苯并咪唑啉酮（1-EBIO）和 6,7-二氯-1H-吲哚-2,3-二酮 3-肟（NS309）已被确认为增加 SK 通道表观 Ca2+ 敏感性的正向门控调节剂。在本研究中，我们将抑制性门控调节描述为一种选择性抑制 SK 通道的新原理。在全细胞贴片钳实验中，化合物 ( R ) -N-（苯并咪唑-2-基）-1,2,3,4-四氢-1-萘胺（NS8593）以约 100 nM 的效力可逆地抑制重组 SK3 介导的电流（人 SK3 和大鼠 SK3）。然而，与已知的孔阻滞剂不同，NS8593 并不抑制 125I-萘胺的结合。使用切除的贴片证明，NS8593 通过将 Ca2+ 激活曲线向右移动来降低 Ca2+ 敏感性，但只对 Ca2+ 激活的最大 SK 电流有轻微影响。NS8593 对所有 SK1-3 亚型都有 Ca2+ 依赖性抑制作用（在 0.5 μM Ca2+ 时，K d = 0.42、0.60 和 0.73 μM），而对中电导和大电导的 Ca2+ 激活 K+ 通道（分别为 hIK 和 hBK 通道）没有影响。NS8593的作用点可从膜的两侧进入，在高浓度的正调制剂NS309存在的情况下，NS8593介导的抑制作用被阻止。在海马切片的小鼠 CA1 神经元上进一步测试表明，NS8593 在 3 μM 的浓度下可抑制对阿帕明和妥布脲敏感的 SK 介导的超极化后电流。

  DOI：

  10.1124/mol.106.027110

文献信息

• Inhibitory Gating Modulation of Small Conductance Ca²⁺-Activated K⁺Channels by the Synthetic Compound (<i>R</i>)<i>-N</i>-(Benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphtylamine (NS8593) Reduces Afterhyperpolarizing Current in Hippocampal CA1 Neurons
  作者：Dorte Strøbæk、Charlotte Hougaard、Tina H. Johansen、Ulrik S. Sørensen、Elsebet Ø. Nielsen、Karin S. Nielsen、Ruth D. T. Taylor、Paola Pedarzani、Palle Christophersen

  DOI：10.1124/mol.106.027110

  日期：2006.11

  SK channels are small conductance Ca2+-activated K+ channels important for the control of neuronal excitability, the fine tuning of firing patterns, and the regulation of synaptic mechanisms. The classic SK channel pharmacology has largely focused on the peptide apamin, which acts extracellularly by a pore-blocking mechanism. 1-Ethyl-2-benzimidazolinone (1-EBIO) and 6,7-dichloro-1 H -indole-2,3-dione 3-oxime (NS309) have been identified as positive gating modulators that increase the apparent Ca2+ sensitivity of SK channels. In the present study, we describe inhibitory gating modulation as a novel principle for selective inhibition of SK channels. In wholecell patch-clamp experiments, the compound ( R ) -N -(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphtylamine (NS8593) reversibly inhibited recombinant SK3-mediated currents (human SK3 and rat SK3) with potencies around 100 nM. However, in contrast to known pore blockers, NS8593 did not inhibit 125I-apamin binding. Using excised patches, it was demonstrated that NS8593 decreased the Ca2+ sensitivity by shifting the activation curve for Ca2+ to the right, only slightly affecting the maximal Ca2+-activated SK current. NS8593 inhibited all the SK1-3 subtypes Ca2+-dependently ( K d = 0.42, 0.60, and 0.73 μM, respectively, at 0.5 μM Ca2+), whereas the compound did not affect the Ca2+-activated K+ channels of intermediate and large conductance (hIK and hBK channels, respectively). The site of action was accessible from both sides of the membrane, and the NS8593-mediated inhibition was prevented in the presence of a high concentration of the positive modulator NS309. NS8593 was further tested on mouse CA1 neurons in hippocampal slices and shown to inhibit the apaminand tubocurarine-sensitive SK-mediated afterhyperpolarizing current, at a concentration of 3 μM.

  SK 通道是小电导 Ca2+ 激活的 K+ 通道，对控制神经元兴奋性、微调发射模式和调节突触机制非常重要。经典的 SK 通道药理学主要集中在多肽阿帕明（apamin）上，它通过孔阻断机制在细胞外发挥作用。1-乙基-2-苯并咪唑啉酮（1-EBIO）和 6,7-二氯-1H-吲哚-2,3-二酮 3-肟（NS309）已被确认为增加 SK 通道表观 Ca2+ 敏感性的正向门控调节剂。在本研究中，我们将抑制性门控调节描述为一种选择性抑制 SK 通道的新原理。在全细胞贴片钳实验中，化合物 ( R ) -N-（苯并咪唑-2-基）-1,2,3,4-四氢-1-萘胺（NS8593）以约 100 nM 的效力可逆地抑制重组 SK3 介导的电流（人 SK3 和大鼠 SK3）。然而，与已知的孔阻滞剂不同，NS8593 并不抑制 125I-萘胺的结合。使用切除的贴片证明，NS8593 通过将 Ca2+ 激活曲线向右移动来降低 Ca2+ 敏感性，但只对 Ca2+ 激活的最大 SK 电流有轻微影响。NS8593 对所有 SK1-3 亚型都有 Ca2+ 依赖性抑制作用（在 0.5 μM Ca2+ 时，K d = 0.42、0.60 和 0.73 μM），而对中电导和大电导的 Ca2+ 激活 K+ 通道（分别为 hIK 和 hBK 通道）没有影响。NS8593的作用点可从膜的两侧进入，在高浓度的正调制剂NS309存在的情况下，NS8593介导的抑制作用被阻止。在海马切片的小鼠 CA1 神经元上进一步测试表明，NS8593 在 3 μM 的浓度下可抑制对阿帕明和妥布脲敏感的 SK 介导的超极化后电流。
• APPLICATION OF TRPM7 INHIBITORS TO TREAT SLEEP APNEA AND HYPERTENSION IN OBESITY
  申请人：THE JOHNS HOPKINS UNIVERSITY

  公开号：US20200054581A1

  公开（公告）日：2020-02-20

  Methods for prevention or treatment of a respiratory disease and a cardiovascular disease in subjects comprising administering to the obese subject an effective amount of TRPM7 inhibitor.
• Synthesis and Structure−Activity Relationship Studies of 2-(N-Substituted)-aminobenzimidazoles as Potent Negative Gating Modulators of Small Conductance Ca²⁺-Activated K⁺ Channels
  作者：Ulrik S. Sørensen、Dorte Strøbæk、Palle Christophersen、Charlotte Hougaard、Marianne L. Jensen、Elsebet Ø. Nielsen、Dan Peters、Lene Teuber

  DOI：10.1021/jm800809f

  日期：2008.12.11

  Small conductance Ca2+-activated K+ channels (SK channels) participate in the control of neuronal excitability, in the shaping of action potential firing patterns, and in the regulation of synaptic transmission. SK channel inhibitors have the potential of becoming new drugs for treatment of various psychiatric and neurological diseases such as depression, cognition impairment, and Parkinson's disease. In the present study we describe the structure-activity relationship (SAR) of a class of 2-(N-substituted)-2-aminobenzimidazoles that constitute a novel class of selective SK channel inhibitors that, in contrast to classical SK inhibitors, do not block the pore of the channel. The pore blocker apamin is not displaced by these compounds in binding studies, and they still inhibit SK channels in which the apamin binding site has been abolished by point mutations. These novel SK inhibitors shift the concentration-response curve for Ca2+ toward higher values and represent the first example of negative gating modulation as a mode-of-action for inhibition of SK channels. The first described compound in this class is NS8593 (14), and the most potent analogue identified in this study is the racemic compound 39 (NS11757), which reversibly inhibits SK3-rnediated currents with a K-d value of 9 nM.