muldamine | 36069-45-1

• 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
• 英文名称: muldamine
• 英文别名: [(3S,8S,9S,10R,13S,14S,16R,17R)-3-hydroxy-10,13-dimethyl-17-[(1S)-1-[(2S,5S)-5-methylpiperidin-2-yl]ethyl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-16-yl] acetate
• CAS: 36069-45-1
• 化学式: C₂₉H₄₇NO₃
• 分子量: 457.697
• InChiKey: ZVYUDNWAHWVPPN-WGMPUXNISA-N

物化性质

• 熔点：
  210.5°C
• 沸点：
  564.13°C (rough estimate)
• 密度：
  1.0275 (rough estimate)
• 颜色/状态：
  Solid
• 溶解度：
  In water, 1.7 mg/L at 25 °C (est)
• 蒸汽压力：
  4.23X10-13 mm Hg at 25 °C (est)
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.9
• 拓扑面积：
  58.6
• 氢给体数：
  2
• 氢受体数：
  4

ADMET

毒理性

• 人类毒性摘录

几种马兜铃属植物与人类和动物的毒性有关。主要毒素是甾体生物碱；有些具有改性的甾体模板，而其他则在于它们的酯化酸部分不同。这些生物碱通过增加神经细胞钠通道的通透性，使它们持续放电。与迷走神经相关联的刺激增加导致被称为贝佐尔德-雅里施反射的三联反应：低血压、心动过缓和呼吸暂停。临床上，各种马兜铃提取物被作为抗高血压药物上市，但由于治疗指数狭窄而被撤出市场。摄入马兜铃生物碱后，预期的体征和症状包括呕吐和腹痛，随后出现心血管效应，如心动过缓、低血压和心脏传导异常甚至死亡。其他哺乳动物摄入这些生物碱后也会出现类似的症状；食用加州马兜铃的动物胎儿可能会出现致畸效应。治疗包括支持性护理，重点是使用液体置换、阿托品和血管加压药来维持血流动力学稳定。症状出现时间在30分钟到4小时之间，病程可能从1天到10天不等；然而，在及时的支持性护理下，患者通常在24小时内完全恢复。

Several species of the Veratrum genus are associated with toxicity in humans and animals. The principal toxins are steroid alkaloids; some have a modified steroid template, whereas others differ in their esterified acid moieties. These alkaloids act by increasing the permeability of the sodium channels of nerve cells, causing them to fire continuously. Increased stimulation, associated with the vagal nerve results in a reflex that causes the triad of responses known as the Bezold-Jarisch reflex: hypotension, bradycardia and apnea. Clinically, various Veratrum extracts were marketed for use as antihypertensive drugs, but because of their narrow therapeutic index were withdrawn from the market. Following the ingestion of Veratrum alkaloids, expected signs and symptoms include vomiting and abdominal pain, followed by cardiovascular effects such as bradycardia, hypotension and cardiac conduction abnormalities and death. Similar symptoms arise in other mammalian species ingesting these alkaloids; teratogenic effects may occur to the fetuses of animals that have grazed on Veratrum californicum. Treatment consists of supportive care, with an emphasis on hemodynamic stability with fluid replacement, atropine and vasopressors. The onset of symptoms occurs between 30 minutes and 4 hours, and the duration of the illness can range from 1 to 10 days; however, with prompt supportive care, patients typically make a full recovery within 24 hours.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：神经毒性/ 从藜芦中提取的十一种生物碱对乌贼和淡水龙虾巨轴突的膜电位和电导率的影响进行了比较。它们可以分为三组。1）藜芦碱、藜芦碱和藜芦原碱A和B会导致膜去极化。活性按此顺序降低，藜芦碱和藜芦碱产生50%最大去极化所需的浓度分别估计为3.3 x 10-5 M和3.7 x 10-3 M。藜芦碱的去极化主要是由于静息状态下膜对钠的透性选择性增加，并且可以被河豚毒素拮抗。所有这些都能有效增强并延长负（去极化）后电位。2）藜芦胺、异藜芦碱、Muldaimine（5-藜芦烷-3-β, 11-α-二醇-11-醋酸酯）和5-藜芦烷-3α-11α-二醇（1x10-4）能够阻断动作电位，而去极化很小或没有。5-藜芦烷-3-β, 11-α-二醇阻断钠和钾电导率的增加。3）环萜胺、藜芦碱、藜芦碱和藜芦碱对静息电位和动作电位没有影响。本文讨论了这些效果的可能的构效关系。

/LABORATORY ANIMALS: Neurotoxicity/ Eleven alkaloids obtained from Veratrum have been compared for their effects on the membrane potential and conductances of squid and crayfish giant axons. They can be classed in three groups. 1) Veratridine, cevadine and protoveratrines A and B cause the membrane to depolarize. The potency decreases in that order, and the concentrations of veratridine and cevadine required for 50% maximum depolarization are estimated to be 3.3 x 10-5 M and 3.7 x 10-3 M, respectively. The depolarization by veratridine is due primarily to a selective increase in resting sodium permeability of time membrane and is antagonized by tetrodotoxin. All of them are effective in augmenting and prolonging the negative (depolarizing) afterpotential. 2) Veratramin, eisorubijervine, muldaimine (5-veratranine 3-beta, 11-alpha-diol-11-acetate) and 5-veratranine-3alpha-11alpha-diol (1x10-4) re capable of blocking the action potential with little or no depolarization. 5-Veratranine-3-beta, 11-alpha-diol blocks both sodium and potassium conductance increases. 3) Cyclopamine, jervine, rubijervine and veratrosine have no effect on the resting and action potentials. Possible structure-activity relationships for these effects are discussed.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：神经毒性/麦达米因在乌贼和淡水龙虾巨轴突中阻断了动作电位，几乎没有或没有去极化。它还阻断了Na和K电导的增加。

/LABORATORY ANIMALS: Neurotoxicity/ Muldamine blocked the action potential with little or no depolarization in squid and crayfish giant axons. It also blocked both Na and K conductance increases.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：发育或生殖毒性/ 从加州藜芦生物碱衍生物，生物碱和11-脱氧生物碱合成的衍生物在类固醇A、B、C和D环中具有不同的功能，以测试哈姆sters类固醇致畸物结构活性的关系。对Muldamine和11-脱乙酰基Muldamine进行了测试，以确定分子中刚性格链的重要性。这些化合物的相对活性表明，它们作为发育中的胚胎中的类固醇激素阻断剂。生物碱的典型螺环生物碱生物碱环系统显然对活性并不重要，而这些生物碱的刚性格链可能仅增强致畸性。具有基本亚胺基团可以进入D环的α面的传统类固醇可能具有相当的致畸性。

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Derivatives of the veratrum californicum alkaloids, jervine & 11-deoxojervine were synthesized with differing functionality in the steroid A, B, C & D rings to test the relation of structure to activity of steroid teratogens in hamsters. Muldamine & 11-deacetylmuldamine were tested to determine the importance of a rigid side chain in the molecule. The relative activities of these compd suggest that they act as steroid hormone blocking agents in the developing embryo. The atypical steroid ring system of jervine spirofuranopiperidine alkaloids apparently is not crucial to activity, & the rigid side chain of these alkaloids may only enhance teratogenicity. Conventional steroids having a basic imino group accessible to the alpha face of the d ring would have a probability of substantial teratogenicity.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  muldamine 在 盐酸 作用下， 以 甲醇 为溶剂， 反应 6.0h， 以32 mg的产率得到Teinemine
  参考文献：
  名称：

  Structure of the steroidal alkaloid muldamine and its deacetyl derivative

  摘要：

  DOI：

  10.1016/0031-9422(82)85214-x

文献信息

• Isolation of Cyclopamine
  申请人：Infinity Pharmaceuticals, Inc.

  公开号：US20160168193A1

  公开（公告）日：2016-06-16

  Provided are deglycosylation methods designed to optimize the yield of a Veratrum alkaloid from Veratrum plant material and/or from an extract of Veratrum plant material.

  提供了去糖化方法，旨在优化从鸢尾科植物材料和/或从鸢尾科植物材料提取物中提取鸢尾科生物碱的产量。
• Regulators of the hedgehog pathway, compositions and uses related thereto
  申请人：Beachy A. Philip

  公开号：US20060128639A1

  公开（公告）日：2006-06-15

  The present invention makes available, inter alia, methods and reagents for modulating smoothened-dependent pathway activation. In certain embodiments, the subject methods can be used to counteract the phenotypic effects of unwanted activation of a hedgehog pathway, such as resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function mutations.

  本发明提供了调节平滑蛋白依赖性通路激活的方法和试剂等。在某些实施例中，这些方法可用于对抗由于刺猬增强功能、ptc失去功能或平滑蛋白增强功能突变引起的刺猬通路不必要激活的表型效应。
• Diversion- and/or abuse-resistant aompositions and methods for making the same
  申请人：Losev Mikhail Viktorovich

  公开号：US20110207761A1

  公开（公告）日：2011-08-25

  A composition formulated for diversion- and/or abuse-resistance, includes at least one active pharmaceutical ingredient (API), each present in an acidic form, a first compound capable of coupling to the acidic form of the API to form a complex, where the resulting complex is resistant to separation by conventional separation methods, and a second compound capable of preferentially coupling to the first compound to thereby release the API from the complex.

  一种旨在防止滥用和/或耐受性的组合物，包括至少一种活性药物成分（API），每种API以酸性形式存在，第一化合物能够与API的酸性形式偶联形成复合物，所得到的复合物对传统的分离方法具有耐受性，以及第二化合物能够优先与第一化合物偶联，从而释放复合物中的API。
• Diversion - And/Or Abuse-Resistant Compositions And Methods For Making The Same
  申请人：Invincible Biotechnology, LLC

  公开号：US20150335593A1

  公开（公告）日：2015-11-26

  A composition formulated for diversion- and/or abuse-resistance, includes at least one active pharmaceutical ingredient (API), each present in an acidic form, a first compound capable of coupling to the acidic form of the API to form a complex, where the resulting complex is resistant to separation by conventional separation methods, and a second compound capable of preferentially coupling to the first compound to thereby release the API from the complex.

  一种旨在防止滥用和/或耐受性的配方，包括至少一种活性药物成分（API），每种成分以酸性形式存在，第一化合物能够与API的酸性形式偶联形成复合物，所得复合物对常规分离方法具有耐受性，第二化合物能够优先与第一化合物偶联，从而释放复合物中的API。
• Use of a decoy protein that interferes with the hedgehog signalling pathway for the manufacture of a medicament for preventing, inhibiting, and/or reversing ocular diseases related with ocular neovascularization
  申请人：Fondazione Telethon

  公开号：EP2123306A1

  公开（公告）日：2009-11-25

  The present invention concerns the use of compounds that interfere with the hedgehog signaling pathway for the manufacture of a medicament for preventing, inhibiting, and/ or reversing ocular diseases related with ocular neovascularization. Partcularly, the above-mentioned diseases are (wet) age-related macular degeneration, (proliferative) diabetic retinopathy, neovascular glaucoma, retinal vein occlusion, or retinopathy of prematurity (ROP).

  本发明涉及使用干扰刺猬信号通路的化合物来制造预防、抑制和/或逆转与眼部新生血管相关的眼部疾病的药物。部分上述疾病是（湿性）老年性黄斑变性、（增殖性）糖尿病视网膜病变、新生血管性青光眼、视网膜静脉闭塞或早产儿视网膜病变（ROP）。