E4031 diHCl

hERG potassium channel

新西兰白兔单个 SAN 细胞的最大舒张电位 (MDP) 被 E-4031 (0.1 ~ 10 μM) 显着去纵向，导致 MDP 去最长作用支架在 1 μM 时从 -58.8±0.9 mV 延长10 μM 时从-24.5±1.8 mV 到-58.2±2.1 到-19.6±1.8 mV[2]。 E-4031 (0.1 ~ 10 μM) 以剂量依赖性方式抑制去极化过程。在新西兰白兔的单个 SAN 细胞中，复杂的部分过程中的部分外部电流和随后的尾电流 (ITD) 导致 ITD 减少 88% [sup] [2]。

Bepridil和E-4031延长了所有左心室层的QT间期和ARI，尽管Mid的延长幅度最大，增加了透壁ARI离散度，特别是在心动过缓期间。与E-4031相比，苄普地尔在缓慢心室起搏期间引起心室复极的轻度反向使用依赖性变化，ARI离散度小于E-4031。这两种药物都增加了ARI（max）和ARI（最大）50%时的周期长度，尽管苄普地尔给药后的变化小于E-4031给药后。每种药物给药后心动过缓未引起VTA；然而，与未接受苄普地尔治疗的狗相比，接受E-4031治疗的五只狗中有两只的交感神经刺激诱导了持续的多态性VTA。
结论：与纯I（kr）阻断剂E-4031不同，苄普地尔表现出较弱的反向使用依赖性，并对交感神经刺激诱导的VTA具有保护作用。这可能是植入式心脏复律除颤器接受者的有效补充治疗。[2]

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在兔单个窦房结肌细胞中研究了延迟整流电流（IK）在脉冲产生中的作用。我们使用了阻断兔心室肌细胞IK的III类抗心律失常药物E-4031。在单个窦房结细胞中，E-4031（0.1μmol/L）显著延长了周期长度和动作电位持续时间，使最大舒张电位去极化，并降低了动作电位的上行速度和舒张去极化率。一半的牢房被完全逮捕。在较高浓度（1和10 mumol/L）下，所有细胞的自发活动都停止了。使用全细胞和两性霉素穿孔贴片技术研究了起搏的三种基本离子电流，即IK、长期内向钙电流（ICa，L）和超极化激活电流（I（f））。E-4031以剂量依赖的方式阻断去极化步骤中的部分外向电流以及随后复极化（ITD）时的尾电流。E-4031（10μmol/L）抑制ITD（88+/-4%）（n=6），降低0 mV时的峰值ICa，L（29+/-15%）（n=4），但不影响I（f）。较低的浓度不影响ICa，L。额外使用5μmol/L硝苯地平表明，ITD部分是由钙敏感电流携带的。有趣的是，完全阻断IK和ICa，L揭示了背景电流分量的存在，其反转电位为-32+/-5.4 mV（n=8），电导率为39.5+/-5.6 pS/pF，因此这既有助于复极化的初始部分，也有助于完全舒张去极化[2]。

通过使用全细胞21和两性霉素穿孔贴片技术记录膜电位和电流。在10个细胞中，只有5个使用了全细胞法，其中研究了0.1μmol/LE-4031的影响。两性霉素穿孔贴片技术用于所有其他实验，以减少细胞内成分的稀释，这可能是膜电流下降的原因。使用垂直的一级贴片电极拉拔器从硼硅酸盐玻璃（外径1mm；管腔内有玻璃纤维）中拉出电极，并进行火抛光。电极电阻在3至5 MΩ之间变化[2]。

Drug Administration[1]
Bepridil, 4 mg/kg, was dissolved in sterile saline and administered intravenously in a single bolus.19 E-4013 was dissolved in sterile saline and administered intravenously in a bolus of 50 μg/kg, followed by a maintenance dose titrated between 5 and 20 μg/kg/min, to match the ARI prolongation induced by bepridil (280–360 ms) during pacing at 140 beats per minute (bpm).20 The data were collected during steady state, beginning 5 minutes after the administration of bepridil, or 5 minutes after the onset of a stable maintenance infusion of E-4031.
Study Protocol and Data Collection[1]
After the creation of complete AV block, the heart was paced at 100 bpm from the RV throughout the experiment.
Completion of the following protocols of (1) and (2) was within 30 minutes.
1) Before the administration of bepridil or E-4031, the surface electrocardiogram, the transmural distribution of ARI, and ARI dispersion were recorded at a pacing cycle length of 428 ms (140 bpm), 500 ms (120 bpm), 600 ms (100 bpm), 750 ms (80 bpm), and 1,000 ms (60 bpm). The measurements were made at steady state, 30 seconds after the onset of each pacing rate.

2) To study the inducibility of VTA, (a) the back-up RV pacing rate was slowed to 40 bpm to allow lengthening of the cardiac cycle to 800–1,500 ms for 60 seconds, and (b) the left stellate ganglion was stimulated for 20 seconds during demand pacing at a cycle length of 750 ms.

Completion of the following protocols of (3) was within 30 minutes.
3) These same protocols (1 and 2) were repeated after the administration of bepridil in five dogs and E-4031 in five other dogs.

[1]. Effects of bepridil versus E-4031 on transmural ventricular repolarization and inducibility of ventricular tachyarrhythmias in the dog. Pacing Clin Electrophysiol. 2010 Aug;33(8):950-9.

[2]. Effects of delayed rectifier current blockade by E-4031 on impulse generation in single sinoatrial nodal myocytes of the rabbit. Circ Res. 1995 Apr;76(4):607-15.

See also: E-4031 (annotation moved to).

C21H29CL2N3O3S

474.4443

473.13

C, 53.16; H, 6.16; Cl, 14.94; N, 8.86; O, 10.12; S, 6.76

113559-13-0

113558-89-7;113559-13-0 (2HCl);

3087190

White to off-white solid powder

561.7ºC at 760 mmHg

293.5ºC

1.21E-12mmHg at 25°C

5.594

87.75

3

6

7

30

603

0

Cl[H].Cl[H].S(C([H])([H])[H])(N([H])C1C([H])=C([H])C(=C([H])C=1[H])C(C1([H])C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])C2=C([H])C([H])=C([H])C(C([H])([H])[H])=N2)C([H])([H])C1([H])[H])=O)(=O)=O

ZQBNWMFBOSOOLX-UHFFFAOYSA-N

InChI=1S/C21H27N3O3S.2ClH/c1-16-4-3-5-19(22-16)12-15-24-13-10-18(11-14-24)21(25)17-6-8-20(9-7-17)23-28(2,26)27;;/h3-9,18,23H,10-15H2,1-2H3;2*1H

N-[4-[1-[2-(6-methylpyridin-2-yl)ethyl]piperidine-4-carbonyl]phenyl]methanesulfonamide dihydrochloride

E-4031; E4031; E 4031; E-4031 dihydrochloride; E-4031; 1-(2-(6-Methyl-2-pyridyl)ethyl)-4-(4-methylsulfonylaminobenzoyl)piperidine dihydrochloride; N-[4-[1-[2-(6-methylpyridin-2-yl)ethyl]piperidine-4-carbonyl]phenyl]methanesulfonamide;dihydrochloride; E-4031 Free; 814AT2BQO7; CHEMBL536480; E4031 2HCl; E-4031 dihydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ≥ 50 mg/mL (~105.39 mM)

配方 1 中的溶解度: 100 mg/mL (210.77 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。