hyoscyamine | 51-55-8

• 物质功能分类: 原料药 - 消化系统用药 - 胃肠解痉药
• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 托烷生物碱
• 英文名称: hyoscyamine
• 英文别名: levsin；Hyoscyamin；L-Hyoscyamine；(8-methyl-8-azabicyclo[3.2.1]octan-3-yl) (2S)-3-hydroxy-2-phenylpropanoate
• CAS: 51-55-8；13269-35-7；16175-85-2；83454-31-3；98302-33-1；131432-21-8；101-31-5
• 化学式: C₁₇H₂₃NO₃
• 分子量: 289.375
• InChiKey: RKUNBYITZUJHSG-LGGPCSOHSA-N

物化性质

• 熔点：
  108,5°C
• 比旋光度：
  D20 -21.0° (alc)
• 沸点：
  431.53°C (rough estimate)
• 密度：
  1.0470 (rough estimate)
• 溶解度：
  DMSO:79.0(最大浓度 mg/mL);273.0(最大浓度 mM)乙醇:58.0(最大浓度 mg/mL);200.43(最大浓度 mM)
• LogP：
  1.380 (est)
• 颜色/状态：
  SILKY, TETRAGONAL NEEDLES FROM EVAPORATING ALCOHOL
• 稳定性/保质期：
  AFFECTED BY LIGHT & HEAT
• 旋光度：
  SPECIFIC OPTICAL ROTATION (ALCOHOL): -21.0 DEG AT 20 °C/D
• 解离常数：
  K= 1.9X10-12 AT 19 °C
• 保留指数：
  2168;2174;2174;2146;2205;2170;2194.7;2146;2168;2174;2170;2210;2192

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

肝脏 半衰期：2-3.5小时

Hepatic Half Life: 2-3.5 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

洋金花碱是一种抗胆碱能药物，具体来说是一种抗毒蕈碱药物，它通过阻断乙酰胆碱在平滑肌、分泌腺体和中枢神经系统副交感神经位点的作用来发挥效果。 洋金花碱在唾液腺、支气管和汗腺以及眼睛、心脏和胃肠道的毒蕈碱受体上与乙酰胆碱竞争性结合具有优势。洋金花碱的作用导致唾液、支气管、胃液和汗腺分泌减少，瞳孔散大，调节麻痹，心率变化，膀胱逼尿肌和胃肠道平滑肌收缩，以及胃肠道蠕动减少。

Hyoscyamine is an anticholinergic, specifically an antimuscarinic, and works by blocking the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the central nervous system. (L1255) Hyoscyamine competes favorably with acetylcholine for binding at muscarinic receptors in the salivary, bronchial, and sweat glands as well as in the eye, heart, and gastrointestinal tract. The actions of hyoscyamine result in a reduction in salivary, bronchial, gastric and sweat gland secretions, mydriasis, cycloplegia, change in heart rate, contraction of the bladder detrusor muscle and of the gastrointestinal smooth muscle, and decreased gastrointestinal motility.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

尽管在过去几十年里被广泛使用，但氢溴酸东莨菪碱并未与肝酶升高或临床上明显的肝脏损伤病例有关联。其安全性较高的一个主要原因是每日剂量较低且使用时限较短。 关于抗胆碱能药物的安全性和潜在肝毒性的参考资料，在抗胆碱能药物概览部分之后会一起给出。 药物类别：胃肠药物；抗胆碱能药物

Despite widespread use over many decades, hyoscyamine has not been linked to episodes of liver enzyme elevations or clinically apparent liver injury. A major reason for its safety may relate to the low daily dose and limited duration of use. References on the safety and potential hepatotoxicity of anticholinergics are given together after the Overview section on Anticholinergic Agents. Drug Class: Gastrointestinal Agents; Anticholinergic Agents

来源:LiverTox

毒理性

• 致癌物分类

对人类无致癌性（未列入国际癌症研究机构IARC清单）。

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

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 健康影响

东莨菪碱影响中枢神经系统。

Hyoscyamine affects the central nervous system. (L1255)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露途径

口服（摄入）（L1817）；皮肤（L1817）。通过舌下给药以及口服给药被完全吸收。

Oral (ingestion) (L1817) ; dermal (L1817). Absorbed totally and completely by sublingual administration as well as oral administration.

来源:Toxin and Toxin Target Database (T3DB)

安全信息

• 危险等级：
  6.1
• 危险品标志：
  T+
• 安全说明：
  S25,S26,S36,S45
• 危险类别码：
  R26/28
• WGK Germany：
  3
• 海关编码：
  2939999090
• RTECS号：
  CK0700000
• 危险品运输编号：
  1544

制备方法与用途

功效作用

莨菪碱广泛存在于多种重要中草药中，包括颠茄、北洋金花和曼陀罗。它具有止痛与解痉的作用，对于坐骨神经痛有较好的疗效，并且有时也被用于治疗癫痫和晕船。

生物活性

Hyoscyamine（天仙子胺）是一种AChR抑制剂，其IC50值为7.5 nM。

Target	Value
AChR	7.5 nM

体外研究

在稳态动力学测量中，L-hyoscyamine使TPase活性的转化数从0.19 min-¹增加到2.11 min-¹。在CHO细胞中，Hyoscyamine能防止兴奋剂诱导的cAMP产生，EC50值为7.8 nM。S-(-)-hyoscyamine可使小鼠心脏（心房和心室）膜中forskolin刺激产生的环AMP合成增加24%。

体内研究

在清醒大鼠体内，L-hyoscyamine (20 mg/kg) 可将移行性肌电复合波(MMC)的循环周期从17.6分钟延长至29.0分钟。

化学性质

Hyoscyamine是一种无臭、苦辣味的白色结晶性粉末。易发生消旋，其水溶液呈碱性。熔点为108.5℃，比旋光度[α]²⁰_D-21°（乙醇）。该物质极易溶于乙醇和稀酸，在氯仿中的溶解度为1：1，在水中可溶（1：280）、在乙醚中易溶（1：69），在苯中亦可溶（1：159）。

用途

Hyoscyamine主要用于生化研究、抗胆碱药及检测金的试剂，也可用于含量测定、鉴定和药理实验等。它通过从颠茄浸膏中提取精制获得。

反应信息

• 作为反应物：
  描述：

  hyoscyamine 、 碘甲烷 以 乙醚 为溶剂， 生成
  参考文献：
  名称：

  Differential analgesic activity of the enantiomers of atropine derivatives does not correlate with their muscarinic subtype selectivity

  摘要：

  The enantiomers of several tropic and p-substituted tropic acid esters related to atropine obtained by esterification under non-racemizing conditions after resolution of the corresponding racemic acids [(+)- and (-)-18, (+)- and (-)-19] are reported. They were tested in vitro on muscarinic subtype receptors and in vivo for their analgesic activity on mice. As in the case of the lead compound, R-(+)-hyoscyamine, these substances show enantioselectivity in analgesic tests, the eutomers being the R-(+) or R-(+)-p-substituted tropic acid derivatives. However, this property, which is a consequence of increased central release of ACh, seems unrelated to muscarinic subtype selectivity insofar as the compounds are unable to discriminate muscarinic subtype receptors. A possible explanation of these results which does not involve subtype selectivity is proposed, based on the recently developed concept of inverse agonism.

  DOI：

  10.1016/s0223-5234(97)83285-0
• 作为产物：
  描述：

  S-托品酸 在 盐酸 、 氯化亚砜 作用下， 反应 30.5h， 生成 hyoscyamine
  参考文献：
  名称：

  Differential analgesic activity of the enantiomers of atropine derivatives does not correlate with their muscarinic subtype selectivity

  摘要：

  The enantiomers of several tropic and p-substituted tropic acid esters related to atropine obtained by esterification under non-racemizing conditions after resolution of the corresponding racemic acids [(+)- and (-)-18, (+)- and (-)-19] are reported. They were tested in vitro on muscarinic subtype receptors and in vivo for their analgesic activity on mice. As in the case of the lead compound, R-(+)-hyoscyamine, these substances show enantioselectivity in analgesic tests, the eutomers being the R-(+) or R-(+)-p-substituted tropic acid derivatives. However, this property, which is a consequence of increased central release of ACh, seems unrelated to muscarinic subtype selectivity insofar as the compounds are unable to discriminate muscarinic subtype receptors. A possible explanation of these results which does not involve subtype selectivity is proposed, based on the recently developed concept of inverse agonism.

  DOI：

  10.1016/s0223-5234(97)83285-0

文献信息

• [EN] 3,5-DIAMINO-6-CHLORO-N-(N-(4-PHENYLBUTYL)CARBAMIMIDOYL) PYRAZINE-2- CARBOXAMIDE COMPOUNDS<br/>[FR] COMPOSÉS 3,5-DIAMINO -6-CHLORO-N-(N- (4-PHÉNYLBUTYL)CARBAMIMIDOYL) PYRAZINE-2-CARBOXAMIDE
  申请人：PARION SCIENCES INC

  公开号：WO2014099673A1

  公开（公告）日：2014-06-26

  The present invention relates compounds of the formula: or pharmaceutically acceptable salts thereof, useful as sodium channel blockers, as well as compositions containing the same, processes for the preparation of the same, and therapeutic methods of use therefore in promoting hydration of mucosal surfaces and the treatment of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, bronchiectasis, acute and chronic bronchitis, emphysema, and pneumonia.

  本发明涉及以下化合物的公式：或其药学上可接受的盐，用作钠通道阻滞剂，以及含有这些化合物的组合物，制备这些化合物的方法，以及在促进粘膜表面水合和治疗包括囊性纤维化、慢性阻塞性肺病、哮喘、支气管扩张、急性和慢性支气管炎、肺气肿和肺炎等疾病的治疗方法。
• CHLORO-PYRAZINE CARBOXAMIDE DERIVATIVES WITH EPITHELIAL SODIUM CHANNEL BLOCKING ACTIVITY
  申请人：Parion Sciences, Inc.

  公开号：US20140171447A1

  公开（公告）日：2014-06-19

  This invention provides compounds of the formula I: and their pharmaceutically acceptable salts, useful as sodium channel blockers, compositions containing the same, therapeutic methods and uses for the same and processes for preparing the same.

  这项发明提供了式I的化合物及其药用盐，可用作钠通道阻滞剂，包含这些化合物的组合物，以及用于这些化合物的治疗方法和用途，以及制备这些化合物的方法。
• Azabicycloalkane compounds
  申请人：——

  公开号：US20040242622A1

  公开（公告）日：2004-12-02

  This invention provides compounds of formula I: 1 wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The compounds of this invention possess both &bgr; 2 adrenergic receptor agonist and muscarinic receptor antagonist activity. Such compounds are useful for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.

  这项发明提供了式I的化合物： 其中R1、R2、R3、R4、R5、R6和R7如规范中所定义，或其药用可接受盐、溶剂或立体异构体。本发明的化合物具有β2肾上腺素受体激动剂和肌碱受体拮抗剂活性。这些化合物对治疗肺部疾病，如慢性阻塞性肺病和哮喘，是有用的。
• Novel Bicyclic Pyridinones
  申请人：Pettersson Martin Youngjin

  公开号：US20120252758A1

  公开（公告）日：2012-10-04

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I as defined herein. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  所述化合物及其药用可接受的盐被披露，其中所述化合物具有如本文所定义的Formula I的结构。相应的药物组合物、治疗方法、合成方法和中间体也被披露。
• Benzimidazolone carboxylic acid derivatives
  申请人：Ando Koji

  公开号：US20050277671A1

  公开（公告）日：2005-12-15

  This invention relates to compounds of the formula (I): wherein R 1 , R 2 , R 3 , A and m are each as described herein or a pharmaceutically acceptable salt or solvate thereof, and compositions containing such compounds and the use of such compounds in the treatment of a condition mediated by 5-HT 4 receptor activity such as, but not limited to, gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders such as cardiac failure and heart arrhythmia, diabetes and apnea syndrome.

  这项发明涉及以下式（I）的化合物： 其中R1、R2、R3、A和m如本文所述，或其药学上可接受的盐或溶剂，以及含有这种化合物的组合物和利用这种化合物治疗由5-HT4受体活性介导的疾病的用途，例如但不限于胃食管反流病、胃肠疾病、胃动力障碍、非溃疡性消化不良、功能性消化不良、肠易激综合征（IBS）、便秘、消化不良、食管炎、胃食管疾病、恶心、中枢神经系统疾病、阿尔茨海默病、认知障碍、呕吐、偏头痛、神经系统疾病、疼痛、心血管疾病如心力衰竭和心律失常、糖尿病和呼吸暂停综合征。