G毒毛旋花苷 | 630-60-4

• 物质功能分类: 原料药 - 循环系统用药 - 抗充血性心力衰竭药
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: G毒毛旋花苷
• 中文别名: G-羊角拗质
• 英文名称: ouabain
• 英文别名: quabain；O3125；g-strophanthin；[3H]-ouabain；strodival；OUA；3-[(1R,3S,5S,8R,9S,10R,11R,13R,14S,17R)-1,5,11,14-tetrahydroxy-10-(hydroxymethyl)-13-methyl-3-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy-2,3,4,6,7,8,9,11,12,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2H-furan-5-one
• CAS: 630-60-4
• 化学式: C₂₉H₄₄O₁₂
• 分子量: 584.661
• InChiKey: LPMXVESGRSUGHW-HBYQJFLCSA-N

物化性质

• 熔点：
  200°C
• 沸点：
  561.69°C (rough estimate)
• 密度：
  1.1941 (rough estimate)
• 溶解度：
  在冷水中的溶解度为10 mg/mL
• 物理描述：
  Ouabain appears as odorless, white crystals or crystalline powder as an octahydrate. Used to produce rapid digitalization in acute congestive heart failure. Also recommended in treatment of atrial or nodal paroxysmal tachycardia and atrial flutter. (EPA, 1998)
• 颜色/状态：
  Crystals from water
• 分解：
  Melts with decomposition at 190 °C.
• 碰撞截面：
  234 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  -1.7
• 重原子数：
  41
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.9
• 拓扑面积：
  207
• 氢给体数：
  8
• 氢受体数：
  12

ADMET

代谢

乌本苷...并未广泛与血浆白蛋白结合，并且...大部分以原形被排出。

Ouabain ... is not bound extensively to plasma albumin and ... /is/ excreted largely unchanged.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

洋地黄苷，是一种固体，是一种常用于实验室进行心肌细胞电生理实验的心脏糖苷。它曾被用作药物和兽药。人类暴露和毒性：洋地黄苷诱导的人类胶质瘤细胞产生反应性氧种和细胞凋亡已有描述。使用(3)H洋地黄苷检测到的洋地黄苷结合位点数量在临界高血压受试者中显著增加，且与遗传无关。内源性洋地黄苷水平在人类原发性高血压中增加。动物研究：动物和孤立视网膜的电视网膜图测量显示，洋地黄苷暴露会迅速降低视网膜活性。兔子的玻璃体内注射导致了快速视力丧失。据报道，洋地黄苷会收缩猫的虹膜周围动脉。洋地黄苷是一种内源性的Na(+)/K(+)-ATP酶抑制剂，其长期给药会导致高血压。在大鼠中，洋地黄苷治疗产生了与双相情感障碍相关的认知缺陷，且独立于运动效应。生态毒性研究：洋地黄苷抑制了隔离的Carcinus鳃从基底外侧到顶侧的氨排出。

IDENTIFICATION AND USE: Ouabain, a solid, is a cardiac glycoside commonly used in the laboratory for electrophysiological experiments in cardiac myocytes. It has been used as medication and as a veterinary drug. HUMAN EXPOSURE AND TOXICITY: Ouabain-induced reactive oxygen species generation and cell apoptosis on human glioma cells has been described. The number of ouabain binding sites, detected using (3)H ouabain, were significantly increased in the borderline hypertensive subjects irrespective of heredity. Endogenous ouabain levels increase in human essential hypertension. ANIMAL STUDIES: Retinal activity measured by electroretinography in animals and in isolated retinas has been shown to be rapidly reduced by exposure to ouabain. Intravitreal injection in rabbits has caused rapid loss of vision. In cats circumferential artery of iris is reported to be constricted by ouabain. Ouabain is an endogenous Na(+)/K(+)-ATPase inhibitor whose chronic administration induces hypertension. Ouabain treatment in rats produced cognitive deficits independent of locomotor effects associated with bipolar disorder. ECOTOXICITY STUDIES: Ouabain inhibited the efflux of ammonia (from the basolateral to the apical side) in preparation of isolated Carcinus gills.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

哇巴因抑制Na-K-ATP酶膜泵，导致细胞内钠和钙浓度增加。细胞内钙浓度的增加可能促进收缩蛋白（例如，肌动蛋白，肌球蛋白）的激活。哇巴因还作用于心脏的电活动，增加阶段4去极化的斜率，缩短动作电位持续时间，并减少最大舒张电位。

Ouabain inhibits the Na-K-ATPase membrane pump, resulting in an increase in intracellular sodium and calcium concentrations. Increased intracellular concentrations of calcium may promote activation of contractile proteins (e.g., actin, myosin). Ouabain also acts on the electrical activity of the heart, increasing the slope of phase 4 depolarization, shortening the action potential duration, and decreasing the maximal diastolic potential.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 相互作用

脑室内注射乌本苷（一种特定的Na-K-ATP酶抑制剂）在大鼠中模拟了双相情感障碍的躁狂表型，因此被认为是最接近躁狂的动物模型之一。双相躁狂已知与内侧前额叶皮层（mPFC）的功能障碍有关，这是参与精神功能的关键大脑区域；然而，这些功能障碍的确切机制尚不清楚。当前研究调查了在SD大鼠mPFC中脑室内注射乌本苷（5微升1毫摩尔乌本苷）后突触传递、突触可塑性和多巴胺释放的变化。电生理学结果显示，乌本苷在mPFC中抑制了短期和长期突触可塑性，分别由成对脉冲促进作用和长时程增强表示。这些乌本苷诱导的突触可塑性变化可以通过预先使用锂（腹腔注射47.5毫克/千克锂，每天两次，连续7天）预防，锂作为一种有效的情绪稳定剂预防躁狂。电化学结果显示，脑室内注射乌本苷增强了mPFC中的多巴胺释放，这不受预先使用锂的影响。这些发现表明，mPFC中的突触可塑性和多巴胺释放的变化可能是乌本苷注射诱导的双相躁狂伴随的mPFC功能障碍的基础。

Intracerebroventricular (ICV) administration of ouabain, a specific Na-K-ATPase inhibitor, in rats mimics the manic phenotypes of bipolar disorder and thus has been proposed as one of the best animal models of mania. Bipolar mania has been known to be associated with dysfunctions of medial prefrontal cortex (mPFC), a brain area critically involved in mental functions; however, the exact mechanism underlying these dysfunctions is not yet clear. The present study investigated synaptic transmission, synaptic plasticity, and dopamine release in Sprague-Dawley rat mPFC following ICV administration of ouabain (5 uL of 1 mM ouabain). The electrophysiological results demonstrated that ouabain depressed the short- and the long-term synaptic plasticity, represented by paired-pulse facilitation and long-term potentiation, respectively, in the mPFC. These ouabain-induced alterations in synaptic plasticity can be prevented by pre-treatment with lithium (intraperitoneal injection of 47.5 mg/kg lithium, twice a day, 7 days), which acts as an effective mood stabilizer in preventing mania. The electrochemical results demonstrated that ICV administration of ouabain enhanced dopamine release in the mPFC, which was not affected by pre-treatment with lithium. These findings suggested that alterations in synaptic plasticity and dopamine release in the mPFC might underlie the dysfunctions of mPFC accompanied with ouabain administration-induced bipolar mania.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

脑源性神经营养因子（BDNF）是一种众所周知且研究充分的神经生长因子。BDNF的大多数生物学效应是通过激活TrkB受体介导的。这种神经生长因子调节多种神经元功能，如细胞增殖、存活和分化。乌本苷是一种与Na(+)/K(+) ATP酶结合的类固醇，能够诱导多种细胞内信号通路的激活。我们团队之前的数据表明，乌本苷处理能够增加视网膜神经节细胞（RGC）的存活率。目前研究的目的是评估这种强心苷是否与BDNF，即视网膜神经节细胞的经典营养因子，具有协同效应，并调查涉及的细胞内信号通路。我们的工作证明了Src、PLC和PKCdelta的激活参与了50 ng/mL BDNF介导的信号级联，因为它们的选择性抑制剂完全阻断了BDNF的营养作用。我们还证明了在使用乌本苷（0.75 nM）和BDNF（10 ng/mL）同时处理时，对RGC存活有协同效应。此外，参与这种协同效应的信号通路包括Src、PLC、PKCdelta和JNK。我们的结果表明，乌本苷和BDNF之间的协同作用是通过激活Src通路、JNK、PLC和PKCdelta实现的。

Brain-derived neurotrophic factor (BDNF) is a well-known and well-studied neurotrophin. Most biological effects of BDNF are mediated by the activation of TrkB receptors. This neurotrophin regulates several neuronal functions as cell proliferation, viability, and differentiation. Ouabain is a steroid that binds to the Na(+)/K(+) ATPase, inducing the activation of several intracellular signaling pathways. Previous data from our group described that ouabain treatment increases retinal ganglion cells survival (RGC). The aim of the present study was to evaluate, if this cardiac glycoside can have a synergistic effect with BDNF, the classical trophic factor for retinal ganglion cells, as well as investigate the intracellular signaling pathways involved. Our work demonstrated that the activation of Src, PLC, and PKCdelta participates in the signaling cascade mediated by 50 ng/mL BDNF, since their selective inhibitors completely blocked the trophic effect of BDNF. We also demonstrated a synergistic effect on RGC survival when we concomitantly used ouabain (0.75 nM) and BDNF (10 ng/mL). Moreover, the signaling pathways involved in this synergistic effect include Src, PLC, PKCdelta, and JNK. Our results suggest that the synergism between ouabain and BDNF occurs through the activation of the Src pathway, JNK, PLC, and PKCdelta.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉注射哇巴因的效果在注射后立即开始，5分钟后达到最大值，持续5-7小时，然后迅速下降。

The effect of i.v.-administered ouabain starts immediately after injection, reaches a maximum after 5 min, last 5-7 hr and then rapidly declines.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

它从消化道吸收不良，口服剂量的大部分似乎被破坏。

It is poorly absorbed from alimentary tract, where much of oral dose appears to be destroyed.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

四、7和10%的(3)H-哇巴因在给豚鼠口服给药后1、5和15小时分别被吸收。在每个3个剂量水平上，吸收百分比是恒定的。...在人体中也得到了类似的结果。...它通过被动扩散从大鼠的胃肠道吸收。肌内剂量（im剂量）的吸收可能更多地取决于组织-血液流动，而不是扩散速率...大鼠30分钟胆汁中有67%的静脉剂量（iv剂量）被排泄。...它从肝脏主动运输到胆汁，而用四氯化碳预处理的大鼠通过抑制这种运输减少了胆汁排泄。

Four, 7 and 10% of (3)H-ouabain had been absorbed 1, 5 and 15 hr respectively after oral administration to guinea pigs. Percentage absorbed was constant at each of 3 dose levels. ... Similar results obtained in man. ... /It/ was absorbed from GI tract of rats by passive diffusion. Absorption of im dose probably depended more on tissue-blood flow than on rates of diffusion ... 67% of iv dose was excreted in 30-min bile of rats. ... /It/ was actively transported from liver to bile, and carbon tetrachloride pretreatment of rats reduced biliary excretion by depressing this transport.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉注射后，大鼠对哇巴因的血浆清除速度比兔和狗快得多。在静脉给药后20分钟测定的血浆、胆汁和肝脏中的放射性水平显示，大鼠的胆汁与血浆浓度比率为1500，而兔（2.9）和狗（9.3）的同一比率要低得多。大鼠的肝/血浆和胆汁/肝脏浓度比率（分别为20和71）也远高于兔（2.5和1.3）或狗（3.3和2.7）。这种种间差异被认为是大鼠相对于兔和狗对哇巴因毒性作用的抵抗力的重要因素。

Plasma clearance of ouabain following iv admin was much faster in rat than in rabbit or dog. Levels of radioactivity in plasma, bile, and liver ... determined 20 min after iv administration ... showed that rat exhibited overall bile to plasma concentration ratio of 1500, whereas same ratio was much less for rabbit (2.9) and dog (9.3). Liver/plasma and bile/liver concentration ratios ... were ... much greater in rat (20 and 71) than in rabbit (2.5 and 1.3) or dog (3.3 and 2.7). This species variation is thought to be important factor in resistance of rat to toxic effects of ouabain relative to rabbit and dog.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  T
• 安全说明：
  S45
• 危险类别码：
  R23/25,R33
• WGK Germany：
  3
• 危险品运输编号：
  UN 1544 6.1/PG 1

制备方法与用途

生物活性

Ouabain (NSC 25485) 是一种选择性的 Na+/K+-ATPase 抑制剂，与 α2/α3 亚基结合，Ki 值分别为 41 nM 和 15 nM。

靶点

Target	Value
α3	15 nM (Ki)
α2	41 nM (Ki)

体外研究

Ouabain 在 100 nM 浓度下抑制 ATPase 活性的 25%。在培养的大鼠星形胶质细胞中，Ouabain (0.1 μM-1.0 μM) 抑制 Na+ 通道活性，在更高浓度（0.5-1.0 mM）时增加 α1 和 β1 mRNA 水平，同时减少 α2 和 β2 mRNA 水平。在对照组和 Ouabain 处理的培养基中，Ouabain 增加 α1 和 β1 的蛋白质表达水平，但不增加 α2 和 β2 表达。

此外，在培养的大鼠星形胶质细胞中，Ouabain 诱导 α1 mRNA 水平上升。环己酰亚胺 (10 mM) 或细胞内 Ca2+ 处理可以抑制这种上调。在两种细胞系（MDCK 和 Ma104）中，Ouabain (10 μM) 均能显著提高 PMD：在 MDCK 细胞中为 28.1%，而在 Ma104 细胞中的效果更为显著（达到 47.9%）。此外，Ouabain 在 MDCK 细胞中还诱导 P-Tyr 持续增加，并导致 GSH 几乎完全恢复；然而，在 Ma104 细胞中这一作用并不显著。

体内研究

Ouabain (14.4 毫克/千克·天，间歇性皮下注射) 能进一步增加由于心肌梗死（MI）导致心脏衰竭大鼠的总外周阻力（TPR）。连续的 Ouabain 注射则使大鼠 TPR 正常化。Ouabain (14.4 毫克/千克·天，连续皮下注射) 显著改善基底和最大 CO：基底为 83 毫升/分钟；最大为 134 毫升/分钟。

类别

有毒物品

毒性分级

剧毒

急性毒性

• 皮下 - 大鼠：LD50: 50 毫克/公斤
• 口服 - 小鼠：LD50: 5 毫克/公斤

可燃性危险特性

不易燃

储运特性

库房通风、低温干燥；与食品分开储运

灭火剂

水、泡沫、二氧化碳、砂土

反应信息

• 作为反应物：
  描述：

  G毒毛旋花苷 在 N-甲基吗啉 、 6C₆H₁₅P*4CF₃O₃S^(1-)*2Ru⁽²⁺⁾ 作用下， 以 2,2,2-三氟乙醇 为溶剂， 反应 11.0h， 以60%的产率得到1-epi-ouabain
  参考文献：
  名称：

  通过转移加氢实现复杂多元醇的定点氧化，胺化和差向异构反应

  摘要：

  带有一个或多个羟基的多氧化碳氢化合物包含大量天然和合成化合物，通常具有强大的生物活性。在合成化学中，醇是羰基的重要前体，然后可以将其转化为多种基于氧或氮的官能团。因此，将天然产物中的单个羟基选择性转化为酮将能够选择性引入非天然官能团。然而，已知的将简单的醇或什至在包含多个受保护的官能团的分子中的醇转化的方法不适用于复杂的多元醇结构的选择性反应。我们提出了一种新型的钌催化剂，该催化剂具有独特的功效，可以选择性氧化多个未保护的多元醇天然产物中的单个羟基。该氧化使得能够将氮基官能团引入缺乏氮原子的这种结构中，并能够通过逐步或可逆的氧化和还原来进行选择性醇差向异构化。

  DOI：

  10.1038/nchem.2835
• 作为产物：
  描述：

  (2R,3R,4R,5S,6S)-2-(((1R,3S,5S,8R,9S,10R,11R,13R,14S,17R)-11-acetoxy-1,5,14-trihydroxy-10-(hydroxymethyl)-13-methyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl tribenzoate 在 sodium carbonate 作用下， 以 甲醇 为溶剂， 反应 1.0h， 以88%的产率得到G毒毛旋花苷
  参考文献：
  名称：

  瓦巴加宁和哇巴因的全合成。

  摘要：

  DOI：

  10.1002/anie.200704959

文献信息

• [EN] HELLEBRIN AND HELLEBRIGENIN DERIVATIVES<br/>[FR] HELLÉBRINE ET DÉRIVÉS D'HELLÉBRIGÉNINE
  申请人：UNIBIOSCREEN SA

  公开号：WO2010102673A1

  公开（公告）日：2010-09-16

  The present invention relates to new cardiotonic Steroid Compounds of Formula (I) or (II) wherein X1, X2, X3, L, R1, R2, R3, R4, and R5 have the same meaning as that defined in the Claims. The invention also relates to the use of said Compounds as medicaments, in particular in the treatment of Cancer.

  本发明涉及具有以下式（I）或（II）的新心力素类化合物，其中X1、X2、X3、L、R1、R2、R3、R4和R5的含义与权利要求中定义的含义相同。该发明还涉及将所述化合物用作药物，特别是用于癌症治疗。
• [EN] IMIDAZOLIUM REAGENT FOR MASS SPECTROMETRY<br/>[FR] RÉACTIF D'IMIDAZOLIUM POUR SPECTROMÉTRIE DE MASSE
  申请人：HOFFMANN LA ROCHE

  公开号：WO2021234004A1

  公开（公告）日：2021-11-25

  The present invention relates to compounds which are suitable to be used in mass spectrometry as well as methods of mass spectrometric determination of analyte molecules using said compounds.

  本发明涉及适用于质谱的化合物，以及利用该化合物进行分析物分子的质谱测定方法。
• Novel Compounds
  申请人：Chhipa Laxmikant

  公开号：US20100168110A1

  公开（公告）日：2010-07-01

  The present invention discloses a novel thyroid like compounds of formula (I), wherein R 1 R 2 , R 3 , R 4 and Z are as defined in the specification, method for its preparation, composition containing such compounds and use of such compounds and composition as medicament. Further, compounds of formula (I) has significantly low binding affinity to thyroid receptors and thus considerably devoid of thyrotoxic effects. The invention also relates to the use of the compound of formula (I) for the preparation of a medicament for treating various disease conditions such as obesity, dyslipidemia, metabolic syndrome and co-morbidities associated with metabolic syndrome.

  本发明公开了一种新型的甲状腺类似化合物，其化学式为（I），其中R1、R2、R3、R4和Z如规范中所定义，以及其制备方法、含有这种化合物的组合物和这种化合物及组合物作为药物的用途。此外，化合物的化学式（I）具有与甲状腺受体显著低的结合亲和力，因此在很大程度上缺乏甲状腺毒性作用。该发明还涉及将化学式（I）的化合物用于制备用于治疗肥胖、血脂异常、代谢综合征以及与代谢综合征相关的合并症等各种疾病状况的药物。
• Potassium Channel Modulators
  申请人：Perez-Medrano Arturo

  公开号：US20120122890A1

  公开（公告）日：2012-05-17

  Disclosed herein are KCNQ potassium channels modulators of formula (I) wherein G 1 , R 2 , R 1a , R 1b , X, X 1 , X 2 , X 3 , R x , J, k, n, q, and t are as defined in the specification. Compositions comprising such compounds; and methods for treating conditions and disorders using such compounds and compositions are also described.

  本文披露了式（I）的KCNQ钾通道调节剂，其中G 1 ，R 2 ，R 1a ，R 1b ，X，X 1 ，X 2 ，X 3 ，R x ，J，k，n，q和t如规范中所定义。还描述了包含这些化合物的组合物；以及使用这些化合物和组合物治疗疾病和疾病的方法。
• Substituted 1,3-thiazole compounds, their production and use
  申请人：——

  公开号：US20040053973A1

  公开（公告）日：2004-03-18

  (1) A 1,3-thiazole compound of which the 5-position is substituted with a 4-pyridyl group having a substituent including no aromatic group or (2) a 1,3-thiazole compound of which the 5-position is substituted with a pyridyl group having at the position adjacent to a nitrogen atom of the pyridyl group a substituent including no aromatic group has an excellent p38 MAP kinase inhibitory activity.

  (1) 一种1,3-噻唑化合物，其5位被取代为含有一个取代基的4-吡啶基团，该取代基不包括芳香基，或者(2) 一种1,3-噻唑化合物，其5位被取代为一个吡啶基团，该吡啶基团的氮原子邻近位置有一个取代基，该取代基不包括芳香基，具有出色的p38 MAP激酶抑制活性。