阿扑吗啡 | 58-00-4

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 阿朴菲
• 中文名称: 阿扑吗啡
• 中文别名: 變嗎啡鹼；阿布吗啡；脱水吗啡
• 英文名称: apomorphin
• 英文别名: APOMORPHINE；R-(-)-apomorphine；(6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol
• CAS: 58-00-4
• 化学式: C₁₇H₁₇NO₂
• mdl: MFCD00070404
• 分子量: 267.327
• InChiKey: VMWNQDUVQKEIOC-CYBMUJFWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  20
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  43.7
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

阿朴吗啡可以通过CYP2B6、2C8、3A4和3A5进行N-去甲基化。它可以通过各种UDP-葡萄糖醛酸基转移酶（UGTs）进行葡萄糖醛酸化，或者通过硫酸转移酶（SULTs）1A1、1A2、1A3、1E1和1B1进行硫酸化。大约60%的舌下阿朴吗啡以硫酸盐结合物的形式被消除，尽管这些硫酸盐结合物的结构并不容易获得。阿朴吗啡剂量的其余部分以阿朴吗啡葡萄糖醛酸苷和去甲阿朴吗啡葡萄糖醛酸苷的形式被消除。只有0.3%的皮下阿朴吗啡以未改变的母药形式被回收。

Apomorphine is N-demethylated by CYP2B6, 2C8, 3A4, and 3A5. It can be glucuronidated by various UGTs, or sulfated by SULTs 1A1, 1A2, 1A3, 1E1, and 1B1. Approximately 60% of sublingual apomorphine is eliminated as a sulfate conjugate, though the structure of these sulfate conjugates are not readily available. The remainder of an apomorphine dose is eliminated as apomorphine glucuronide and norapomorphine glucuronide. Only 0.3% of subcutaneous apomorphine is recovered as the unchanged parent drug.

来源:DrugBank

代谢

人类阿朴吗啡代谢途径尚不清楚。潜在的代谢途径包括硫酸化、N-去甲基化、葡萄糖醛酸化和氧化。1 阿朴吗啡在体外迅速自动氧化。细胞色素P-450（CYP）酶在阿朴吗啡的代谢中仅起轻微作用。体外研究表明，阿朴吗啡可能通过COMT代谢。来自体内研究的数据表明，阿朴吗啡不被COMT代谢。

Routes of apomorphine metabolism in humans are not known. Potential metabolic routes include sulfation, N-demethylation, glucuronidation, and oxidation.1 Apomorphine undergoes rapid auto-oxidation in vitro. Cytochrome P-450 (CYP) enzymes play a minor role in the metabolism of apomorphine. In vitro studies have suggested that apomorphine may be metabolized by COMT. Data from in vivo studies indicate that apomorphine is not metabolized by COMT.

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏 半衰期：40分钟（范围30 - 60分钟）

Hepatic Half Life: 40 minutes (range 30 - 60 minutes)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

阿朴吗啡作为帕金森病治疗的确切作用机制尚不清楚，尽管人们认为这可能是由于刺激大脑内突触后的多巴胺D2型受体。研究表明，阿朴吗啡在帕金森病动物模型中能改善运动功能。特别是，阿朴吗啡能减弱由神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）在大脑中上升的黑质纹状体多巴胺能通路损伤所引起的运动缺陷。

The precise mechanism of action of apomorphine as a treatment for Parkinson's disease is unknown, although it is believed to be due to stimulation of post-synaptic dopamine D2-type receptors within the brain. Apomorphine has been shown to improve motor function in an animal model of Parkinson's disease. In particular, apomorphine attenuates the motor deficits induced by lesions in the ascending nigrostriatal dopaminergic pathway with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in primates.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

阿朴吗啡尚未有报道称会导致血清转氨酶升高或临床上明显的急性肝损伤，但它的使用受到了限制，通常以低剂量短期给药。因此，如果阿朴吗啡导致肝损伤，那一定是罕见的。

Apomorphine has not been reported to cause serum aminotransferase elevations or clinically apparent acute liver injury, but its use has been limited and is typically given in low doses for a limited period of time. Thus, if apomorphine causes liver injury it must be rare.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：阿扑吗啡

Compound:apomorphine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：无匹配

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

阿朴吗啡的血浆Tmax为10-20分钟，并且有脑脊液Tmax。阿朴吗啡的Cmax和AUC在患者之间有显著差异，据报道有5到10倍的区别。

Apomorphine has a plasma Tmax of 10-20 minutes and a cerebrospinal fluid Tmax. The Cmax and AUC of apomorphine vary significantly between patients, with 5- to 10-fold differences being reported.

来源:DrugBank

吸收、分配和排泄

• 消除途径

阿朴吗啡的消除途径数据并不容易获得。一项对大鼠的研究显示，阿朴吗啡主要在尿液中消除。

Data regarding apomorphine's route of elimination is not readily available. A study in rats has shown apomorphine is predominantly eliminated in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

皮下注射阿扑吗啡的表观分布容积为123-404升，平均为218升。舌下含服阿扑吗啡的表观分布容积为3630升。

The apparent volume of distribution of subcutaneous apomorphine is 123-404L with an average of 218L. The apparent volume of distribution of sublingual apomorphine is 3630L.

来源:DrugBank

吸收、分配和排泄

• 清除

舌下给药15毫克阿扑吗啡的清除率是1440升/小时，而静脉注射给药的清除率是223升/小时。

The clearance of a 15mg sublingual dose of apomorphine is 1440L/h, while the clearance of an intravenous dose is 223L/h.

来源:DrugBank

吸收、分配和排泄

血浆与全血阿朴吗啡浓度比值等于一。分布容积的平均值（范围）为218升（123 - 404升）。脑脊液（CSF）中的最大浓度小于最大血浆浓度的10%，并且出现在10到20分钟后。

The plasma-to-whole blood apomorphine concentration ratio is equal to one. Mean (range) apparent volume of distribution was 218 L (123 - 404 L). Maximum concentrations in cerebrospinal fluid (CSF) are less than 10% of maximum plasma concentrations and occur 10 to 20 minutes later.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  阿扑吗啡 在 bis-triphenylphosphine-palladium(II) chloride 咪唑 、 甲酸 、 三正丁胺 、 1,3-双(二苯基膦)丙烷 、 potassium carbonate 、 三乙胺 作用下， 以 氢氟酸 、 N,N-二甲基甲酰胺 为溶剂， 反应 96.0h， 生成 [(6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-10-yl]oxy-tert-butyl-diphenylsilane
  参考文献：
  名称：

  A SIMPLE REGIOSELECTIVE SYNTHESIS OF (R)-10-HYDROXYAPORPHINE DIRECTLY FROM (R)-10,11-DIHYDROXYAPORPHINE [(R)-APOMORPHINE]

  摘要：

  DOI：

  10.1080/00304949809355296
• 作为产物：
  描述：

  吗啡 在 甲烷磺酸 作用下， 反应 0.12h， 以81%的产率得到阿扑吗啡
  参考文献：
  名称：

  Synthesis, functional and binding profile of (R)-apomorphine based homobivalent ligands targeting the dopamine D2 receptor

  摘要：

  双价配体是研究GPCR二聚化现象的有用工具。我们基于（R）-阿朴吗啡合成了不同间隔区长度的双价配体，并在多巴胺D2受体上通过功能性和结合试验评估了这些化合物。结果展示了针对D2R的双价配体的新型结构活性关系，并揭示了间隔区长度与配体效能、效力和亲和力之间的关系。

  DOI：

  10.1039/c3md00154g

文献信息

• [EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2016089721A1

  公开（公告）日：2016-06-09

  The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及甲基噁唑化合物，其为促进睡眠的受体拮抗剂。本发明还涉及所述化合物在潜在治疗或预防涉及促进睡眠的神经和精神疾病和疾病中的用途。本发明还涉及包含这些化合物的组合物。本发明还涉及这些组合物在潜在预防或治疗涉及促进睡眠的疾病中的用途。
• HETEROBICYCLIC COMPOUNDS
  申请人：Amgen Inc.

  公开号：US20130225552A1

  公开（公告）日：2013-08-29

  Heterobicyclic compounds of Formula (I): or a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as defined in the specification, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, Huntington's Disease, and the like.

  Formula (I)的杂环化合物： 或其药用可接受的盐、互变异构体或立体异构体，如规范中所定义，并含有它们的组合物，以及制备这种化合物的方法。本文还提供了通过抑制PDE10来治疗由此可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症、亨廷顿病等。
• [EN] 3-ARYLOXY/ THIO-2, 3-SUBSTITUTED PROPANAMINES AND THEIR USE IN INHIBITING SEROTONIN AND NOREPINEPHRINE REUPTAKE<br/>[FR] 3-ARYLOXY/THIO-2, 3-SUBSTITUE PROPANAMINES ET LEUR UTILISATION POUR INHIBER LE RECAPTAGE DE LA SEROTONINE ET DE LA NOREPINEPHRINE
  申请人：LILLY CO ELI

  公开号：WO2004043903A1

  公开（公告）日：2004-05-27

  There is provided a compound of formula (I) wherein A is selected from -O- and -S-; X is selected from phenyl optionally substituted with up to 5 substituents each independently selected from halo, C1-C4 alkyl and C1-C4 alkoxy, thienyl optionally substituted with up to 3 substituents each independently selected from halo and C1-C4 alkyl, and C2-C8 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl and C4-C8 cycloalkylalkyl, each of which may be optionally substituted with up to 3 substituents each independently selected from halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl-S(O)n- where n is 0, 1 or 2, -CF3, -CN and -CONH2; Y is selected from phenyl, naphthyl, dihydrobenzothienyl, benzothiazolyl, benzoisothiazolyl, quinolyl, isoquinolyl, naphthyridyl, thienopyridyl, indanyl, 1,3-benzodioxolyl, benzothienyl, indolyl and benzofuranyl, each of which may be optionally substituted with up to 4 or, where possible, up to 5 substituents each independently selected from halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl-S(O)n- where n is 0, 1 or 2, nitro, acetyl, -CF3, -SCF3 and cyano; and when Y is indolyl it may be substituted or further substituted by an N-substituent selected from C1-C4 alkyl; Z is selected from OR3 or F, wherein R3 is selected from H, C1-C6 alkyl and phenyl C1-C6 alkyl; R1 and R2 are each independently H or C1-C4 alkyl; and pharmaceutically acceptable salts thereofwith the proviso that when Y is optionally substituted phenyl or optionally substituted 1,3-benzodioxolyl and Z is OR3 and X is optionally substituted phenyl then A is -S-.

  提供一种化合物，其化学式为（I），其中A从-O-和-S-中选择；X从苯基选项地取代，每个取代基可独立地从卤素、C1-C4烷基和C1-C4烷氧基中选择最多5个取代基，噻吩基选项地取代，每个取代基可独立地从卤素和C1-C4烷基中选择最多3个取代基，以及C2-C8烷基、C2-C8烯基、C3-C8环烷基和C4-C8环烷基烷基，每个基可选地取代，每个取代基可独立地从卤素、C1-C4烷基、C1-C4烷氧基、C1-C4烷基-S(O)n-（其中n为0、1或2）、-CF3、-CN和-CONH2中选择；Y从苯基、萘基、二氢苯并噻吩基、苯并噻唑基、苯并异噻唑基、喹啉基、异喹啉基、萘啉基、噻吩吡啉基、茚基、1,3-苯并二氧杂环戊基、苯并噻吩基、吲哚基和苯并呋喃基中选择，每个基可选地取代，最多可独立地从卤素、C1-C4烷基、C1-C4烷氧基、C1-C4烷基-S(O)n-（其中n为0、1或2）、硝基、乙酰基、-CF3、-SCF3和氰基中选择最多4个或在可能的情况下最多5个取代基；当Y为吲哚基时，它可以被取代或进一步被N-取代基取代，N-取代基从C1-C4烷基中选择；Z从OR3或F中选择，其中R3从H、C1-C6烷基和苯基C1-C6烷基中选择；R1和R2各自独立地为H或C1-C4烷基；以及其药学上可接受的盐，但有一个条件，即当Y为可选地取代的苯基或可选地取代的1,3-苯并二氧杂环戊基，Z为OR3且X为可选地取代的苯基时，A为-S-。
• IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AND THEIR USE AS PDE10 INHIBITORS
  申请人：Pastor-Fernández Joaquin

  公开号：US20110269752A1

  公开（公告）日：2011-11-03

  The present invention relates to novel imidazo[1,2- b ]pyridazine derivatives which are inhibitors of the phosphodiesterase 10 enzyme (PDE10) and which are useful for the treatment or prevention of neurological, psychiatric and metabolic disorders in which the PDE10 enzyme is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, to the use of such compounds or pharmaceutical compositions for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases.

  本发明涉及新型咪唑并[1,2-b]吡啶嗪衍生物，其为磷酸二酯酶10（PDE10）的抑制剂，并且适用于治疗或预防涉及PDE10酶的神经、精神和代谢紊乱。该发明还涉及包含这种化合物的药物组合物，用于制备这种化合物和组合物的方法，以及利用这种化合物或药物组合物预防或治疗神经、精神和代谢紊乱和疾病。
• Acetamides and benzamides that are useful in treating sexual dysfunction
  申请人：——

  公开号：US20040029887A1

  公开（公告）日：2004-02-12

  The present invention relates to the use of compounds of formula (I) 1 for the treatment of sexual dysfunction and to compositions containing compounds of formula (I) for the treatment of sexual dysfunction.

  本发明涉及使用式(I)的化合物治疗性功能障碍，以及含有式(I)化合物的组合物用于治疗性功能障碍。