[(1S)-1-[(1R,5R,6S,11S,12R,14R)-9,12-dihydroxy-6,16-dimethyl-10,19-dioxa-16-azahexacyclo[12.5.3.15,9.01,14.02,11.06,11]tricosa-2,21-dien-22-yl]ethyl] 2,4-dimethyl-1H-pyrrole-3-carboxylate | 23509-16-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: [(1S)-1-[(1R,5R,6S,11S,12R,14R)-9,12-dihydroxy-6,16-dimethyl-10,19-dioxa-16-azahexacyclo[12.5.3.15,9.01,14.02,11.06,11]tricosa-2,21-dien-22-yl]ethyl] 2,4-dimethyl-1H-pyrrole-3-carboxylate
• CAS: 23509-16-2
• 化学式: C₃₁H₄₂N₂O₆
• 分子量: 538.7
• InChiKey: ISNYUQWBWALXEY-LKKHGHOQSA-N

物化性质

• 比旋光度：
  24584 -5 To -10°; 24300 -260° (c = 0.23 in methanol)
• 沸点：
  614.87°C (rough estimate)
• 密度：
  1.1575 (rough estimate)
• 颜色/状态：
  Noncrystal
• 溶解度：
  In water, 2.8 mg/L at 25 °C (est)
• 蒸汽压力：
  7.49X10-16 mm Hg at 25 °C (est)
• 旋光度：
  Specific optical rotation: - 5 to -10 deg at 24 degC/584 °C; -260 deg at 24 °C/300 °C (c = 0.23 in methanol)
• 腐蚀性：
  538.60
• 解离常数：
  pKa = 7.45

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  39
• 可旋转键数：
  4
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  104
• 氢给体数：
  3
• 氢受体数：
  7

ADMET

毒理性

• 相互作用

两种不同类型的局部麻醉药（LAs）之前已被发现能够阻断蝙蝠毒素（BTX）修饰的Na+通道：类型1 LAs，如可卡因和布比卡因，优先与开放通道相互作用，而类型2 LAs，如苯佐卡因和三卡因，与失活通道相互作用。本文中，我们描述了第三种类型的LA，以四卡因为代表的的双重阻断剂，它与关闭通道强烈结合，但当膜去极化时，也会在一定程度上与开放通道结合。通过稳态失活测量和剂量反应曲线确定了四卡因增强BTX修饰Na+通道的失活。在稳态失活最大的-70 mV时，50%抑制浓度（IC50）估计为5.2微M，希尔系数为0.98，表明一个四卡因分子与一个失活通道结合。当膜去极化时，四卡因也与Na+通道有效相互作用；在+50 mV时的IC50估计为39.5微M，希尔系数为0.94。出乎意料的是，发现带电的四卡因是阻断失活通道的主要活性形式。此外，外部Na+离子似乎拮抗了四卡因对失活通道的阻断。与这些结果一致，N-丁基四卡因季铵盐，一种永久带电的四卡因衍生物，仍然是一个强烈的失活增强剂。另一种四卡因衍生物，2-(二甲基氨基)乙基苯甲酸盐，在苯环上缺少4-丁氨基功能团，其阻断作用比四卡因弱大约100倍。我们推测：1）失活增强剂的结合位点位于Na+渗透途径内，2）外部Na+离子通过静电排斥拮抗失活增强剂的阻断，3）苯环上的4-丁氨基功能团对于阻断和增强失活至关重要，4）Na+孔内可能存在失活增强剂和开放通道阻断剂的重叠结合位点。

Two distinct types of local anesthetics (LAs) have previously been found to block batrachotoxin (BTX)-modified Na+ channels: type 1 LAs such as cocaine and bupivacaine interact preferentially with open channels, whereas type 2 LAs, such as benzocaine and tricaine, with inactivated channels. Herein, we describe our studies of a third type of LA, represented by tetracaine as a dual blocker that binds strongly with closed channels but also binds to a lesser extent with open channels when the membrane is depolarized. Enhanced inactivation of BTX-modified Na+ channels by tetracaine was determined by steady-state inactivation measurement and by the dose-response curve. The 50% inhibitory concentration (IC50) was estimated to be 5.2 microM at -70 mV, where steady-state inactivation was maximal, with a Hill coefficient of 0.98 suggesting that one tetracaine molecule binds with one inactivated channel. Tetracaine also interacted efficiently with Na+ channels when the membrane was depolarized; the IC50 was estimated to be 39.5 microM at +50 mV with a Hill coefficient of 0.94. Unexpectedly, charged tetracaine was found to be the primary active form in the blocking of inactivated channels. In addition, external Na+ ions appeared to antagonize the tetracaine block of inactivated channels. Consistent with these results, N-butyl tetracaine quaternary ammonium, a permanently charged tetracaine derivative, remained a strong inactivation enhancer. Another derivative of tetracaine, 2-(di-methylamino) ethyl benzoate, which lacked a 4-butylamino functional group on the phenyl ring, elicited block that was approximately 100-fold weaker than that of tetracaine. We surmise that 1) the binding site for inactivation enhancers is within the Na+ permeation pathway, 2) external Na+ ions antagonize the block of inactivation enhancers by electrostatic repulsion, 3) the 4-butylamino functional group on the phenyl ring is critical for block and for the enhancement of inactivation, and 4) there are probably overlapping binding sites for both inactivation enhancers and open-channel blockers within the Na+ pore

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

目的：为了研究不同钠通道亚型对全身麻醉剂的反应，我们检查了戊巴比妥（一种与硫喷妥钠密切相关的类似物）对来自人类骨骼肌的单个钠通道的影响，并将其与来自人类大脑和人类心室肌通道的现有数据进行了比较。方法：将从人类骨骼肌制备中提取的钠通道纳入平面脂质双层中，在蝙蝠毒碱（一种钠通道激活剂）存在的情况下，检查单个钠通道的稳态行为及其对戊巴比妥的反应。在戊巴比妥（0.34-1.34 mM）加入之前和之后记录单通道电流。结果：在对称的500 mM NaCl中，人类骨骼肌钠通道的平均单通道电导为21.0 +/- 0.6 pS，通道的开放时间分数为0.96 +/- 0.04。激活中点电位为-96.2 +/- 1.6 mV。细胞外四膜虫毒素以半最大浓度（k1/2 = 60 nM）在0 mV时阻断通道。戊巴比妥以浓度依赖性方式减少了单个骨骼肌钠通道的时间平均电导（抑制浓度50% [IC50] = 0.66 mM）。稳态激活被转移到更超极化的电位（在0.67 mM戊巴比妥时为-16.7 mV）。结论：在平面脂质双层系统中，骨骼肌钠通道具有一些与心脏或中枢神经系统组织的钠通道相比显著不同的电生理特性。与控制数据相比，这些不同的人类钠通道亚型对全身麻醉剂戊巴比妥表现出相同的质量和数量反应。这些效果对整体麻醉的含义将取决于个体通道在其神经网络中的作用，但抑制中枢神经系统和外周钠通道可能会增加全身麻醉效果。

PURPOSE: To investigate the response to general anesthetics of different sodium-channel subtypes, we examined the effects of pentobarbital, a close thiopental analogue, on single sodium channels from human skeletal muscle and compared them to existing data from human brain and human ventricular muscle channels. METHODS: Sodium channels from a preparation of human skeletal muscle were incorporated into planar lipid bilayers, and the steady-state behavior of single sodium channels and their response to pentobarbital was examined in the presence of batrachotoxin, a sodium-channel activator. Single-channel currents were recorded before and after the addition of pentobarbital (0.34-1.34 mM). RESULTS: In symmetrical 500 mM NaCl, human skeletal muscle sodium channels had an averaged single-channel conductance of 21.0 +/- 0.6 pS, and the channel fractional open time was 0.96 +/- 0.04. The activation midpoint potential was -96.2 +/- 1.6 mV. Extracellular tetrodotoxin blocked the channel with a half-maximal concentration (k1/2) of 60 nM at 0 mV. Pentobarbital reduced the time-averaged conductance of single skeletal muscle sodium channels in a concentration-dependent manner (inhibitory concentration 50% [IC50] = 0.66 mM). The steady-state activation was shifted to more hyperpolarized potentials (-16.7 mV at 0.67 mM pentobarbital). CONCLUSION: In the planar lipid bilayer system, skeletal muscle sodium channels have some electrophysiological properties that are significantly different compared with those of sodium channels from cardiac or from central nervous tissue. In contrast to the control data, these different human sodium channel subtypes showed the same qualitative and quantitative response to the general anesthetic pentobarbital. The implication of these effects for overall anesthesia will depend on the role the individual channels play within their neuronal networks, but suppression of both central nervous system and peripheral sodium channels may add to general anesthetic effects

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

我们已经研究了普鲁卡因酰胺对牛心和鼠骨骼肌的BTX激活钠通道的作用。当应用于细胞内侧时，普鲁卡因酰胺引起了快速的、开放通道的阻塞。我们使用幅度分布分析估计了速率常数。膜去极化增加了阻塞速率并减慢了解除阻塞。速率常数在大小和电压依赖性方面在心肌肉和骨骼肌通道中相似。从性质上讲，这种阻塞类似于利多卡因引起的快速开放通道阻塞，但普鲁卡因酰胺的效力大约低七倍。分子建模表明，普鲁卡因酰胺和利多卡因之间的效力差异可能源于它们的芳香环的相对取向，或者来自芳基-胺链接结构的差异。对于心脏通道，普鲁卡因酰胺减少了过渡到长期闭合状态的概率，这种状态表现出失活特征。动力学识别的闭合状态的 平均持续时间没有受到影响。快速阻塞的程度和抑制慢闭合的程度是相关的。内部应用的QX-314，一种利多卡因衍生物，也是一种快速阻塞剂，产生了类似的效果。因此，药物结合到快速阻塞位点似乎抑制了BTX激活的心脏通道的失活。

We have investigated the action of procainamide on batrachotoxin (BTX)-activated sodium channels from bovine heart and rat skeletal muscle. When applied to the intracellular side, procainamide induced rapid, open-channel block. We estimated rate constants using amplitude distribution analysis. Membrane depolarization increased the blocking rate and slowed unblock. The rate constants were similar in both magnitude and voltage dependence for cardiac and skeletal muscle channels. Qualitatively, this block resembled the fast open-channel block by lidocaine, but procainamide was about sevenfold less potent. Molecular modeling suggests that the difference in potency between procainamide and lidocaine might arise from the relative orientation of their aromatic rings, or from differences in the structure of the aryl-amine link. For the cardiac channels, procainamide reduced the frequency of transitions to a long-lived closed state which shows features characteristic of inactivation. Mean durations of kinetically identified closed states were not affected. The degree of fast block and of inhibition of the slow closures were correlated. Internally applied QX-314, a lidocaine derivative and also a fast blocker, produced a similar effect. Thus, drug binding to the fast blocking site appears to inhibit inactivation in BTX-activated cardiac channels.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

本研究的目的旨在研究爪蟾毒素（BTX）对心肌细胞钠通道特性的影响，包括通道门控和动力学的变化，以及对局部麻醉剂阻断的敏感性。我们使用膜片钳技术的全细胞配置来测量豚鼠心肌细胞的钠电流。为了保持良好的电压控制，我们将细胞外钠浓度和温度降低（5-10 mM，17°C）。我们的结果显示：1）BTX修饰心肌INa，导致产生大量的稳态（非失活）成分的INa；2）BTX对心肌钠通道的修饰使激活电位更负，并减少最大gNa和对钠的选择性；3）BTX与其在心肌钠通道上的受体的结合降低了局部麻醉剂对其结合点的亲和力；4）BTX修饰的通道显示出局部麻醉剂的使用依赖性阻断。局部麻醉剂对BTX修饰的钠通道的阻断效力降低可能是由于BTX与局部麻醉剂在钠通道上的各自结合位点之间的别构相互作用。我们观察到局部麻醉剂的使用依赖性阻断在BTX修饰的钠通道中持续存在，这表明在这种形式的外部阻断可以在几乎没有失活状态的情况下发生。因此，使用依赖性阻断的发展似乎主要依赖于在这些条件下局部麻醉剂与激活的钠通道的结合。

The purpose of the present study was to examine the characteristics of Na+ channel modification by batrachotoxin (BTX) in cardiac cells, including changes in channel gating and kinetics as well as susceptibility to block by local anesthetic agents. We used the whole cell configuration of the patch clamp technique to measure Na+ current in guinea pig myocytes. Extracellular Na+ concentration and temperature were lowered (5-10 mM, 17 degrees C) in order to maintain good voltage control. Our results demonstrated that 1) BTX modifies cardiac INa, causing a substantial steady-state (noninactivating) component of INa, 2) modification of cardiac Na+ channels by BTX shifts activation to more negative potentials and reduces both maximal gNa and selectivity for Na+; 3) binding of BTX to its receptor in the cardiac Na+ channel reduces the affinity of local anesthetics for their binding site; and 4) BTX-modified channels show use-dependent block by local anesthetics. The reduced blocking potency of local anesthetics for BTX-modified Na+ channels probably results from an allosteric interaction between BTX and local anesthetics for their respective binding sites in the Na+ channel. Our observations that use-dependent block by local anesthetics persists in BTX-modified Na+ channels suggest that this form of extra block can occur in the virtual absence of the inactivated state. Thus, the development of use-dependent block appears to rely primarily on local anesthetic binding to activated Na+ channels under these conditions.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：蝙蝠毒素是一种神经毒性的甾体生物碱，最初从哥伦比亚的毒箭蛙中分离出来，后来在巴布亚新几内亚的某些鸣禽中发现。人们认为这两个脊椎动物群体都不会从头开始产生毒素，而是可能从饮食来源中获取它们。人类研究：蝙蝠毒素是调节电压门控钠通道的强效剂，导致神经和肌肉的不可逆去极化，纤维颤动，心律失常，最终导致心脏衰竭。自从其被发现以来，田野研究人员还报告说，当他们的皮肤接触到这种毒素后，会出现麻木感。动物研究：当P. terribilis在笼养中时，蝙蝠毒素的水平往往会降低，但即使被限制在笼中长达6年，这些青蛙的毒性仍然是当地人用于毒害吹管箭头的其他Phyllobates物种的至少五倍。在笼养中成熟的第一代后代中检测不到蝙蝠毒素。从野外捕获的青蛙和非毒性的第一代青蛙的神经和肌肉样本都对蝙蝠毒素不敏感。控制钠通道激活和渗透性的调节位点似乎已经最小化地改变，以防止与蝙蝠毒素的相互作用，但仍然对其他钠传导激活剂（如藜芦碱、灰毛毒素）敏感，而这些激活剂青蛙在自然环境中不会接触到。

IDENTIFICATION AND USE: Batrachotoxins are neurotoxic steroidal alkaloids first isolated from a Colombian poison-dart frog and later found in certain passerine birds of New Guinea. Neither vertebrate group is thought to produce the toxins de novo, but instead they likely sequester them from dietary sources. HUMAN STUDIES: Batrachotoxin is a potent modulator of voltage-gated sodium channels, leading to irreversible depolarization of nerves and muscles, fibrillation, arrhythmias and eventually cardiac failure. Since its discovery, field researchers also reported numbness after their skin came into contact with this toxin. ANIMAL STUDIES: Levels of batrachotoxin tend to be reduced when P. terribilis is maintained in captivity, but even after being confined for up to 6 years, these frogs were still at least five times more toxic than other Phyllobates species used by natives for poisoning blowgun darts. Batrachotoxin was not detectable in F1 progeny reared to maturity in captivity. Nerve and muscle preparations from wild-caught frogs and from the nontoxic F1 frogs were both insensitive to batrachotoxin. The regulatory site controlling sodium-channel activation and permeability appears to have been minimally altered to prevent interaction with batrachotoxin, but is still sensitive to other sodium conductance activators (veratridine, grayanotoxin) to which the frogs are not exposed naturally.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(b)
• 危险品运输编号：
  UN 3172
• 包装等级：
  III
• 危险类别：
  6.1(b)

制备方法与用途

类别：有毒物质

• 毒性分级：剧毒
• 急性毒性：
  • 腹腔注射（小鼠）LD₅₀：0.002 毫克/公斤
  • 皮下注射（小鼠）LD₅₀：0.002 毫克/公斤

可燃性危险特性：

• 可燃，燃烧时会产生有毒氮氧化物烟雾。

储运特性：

• 通风、低温干燥保存；
• 应与库房食品原料分开存放。

灭火剂：

• 水
• 二氧化碳
• 干粉
• 砂土