[(3S,6S)-6-二甲氨基-4,4-二苯基-庚烷-3-基]乙酸酯 | 1477-40-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: [(3S,6S)-6-二甲氨基-4,4-二苯基-庚烷-3-基]乙酸酯
• 中文别名: 左醋美沙朵
• 英文名称: (+/-)-threo-5-acetoxy-2-dimethylamino-4,4-diphenyl-heptane
• 英文别名: (+/-)-threo-5-Acetoxy-2-dimethylamino-4,4-diphenyl-heptan；(+/-)-threo-6-Dimethylamino-3-acetoxy-4.4-diphenyl-heptan；Levomethadyl acetate；[(3S,6S)-6-(dimethylamino)-4,4-diphenylheptan-3-yl] acetate
• CAS: 1477-40-3
• 化学式: C₂₃H₃₁NO₂
• 分子量: 353.505
• InChiKey: XBMIVRRWGCYBTQ-AVRDEDQJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  26
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  3

ADMET

代谢

醋酸左旋甲丙氨酯被去甲基化为诺左旋甲丙氨酯，然后再次去甲基化为二诺左旋甲丙氨酯。这种广泛的首次通过代谢产生了2种比母药活性更强的代谢物。

Levomethadyl acetate is demethylated to nor-levomethadyl acetate which is again demethylated to dinor-levomethadyl acetate. This extensive first pass metabolism produces 2 metabolites that are more active than the parent drug.

来源:DrugBank

代谢

醋酸左旋甲丙氨酯在首次通过肝脏时会被广泛代谢为其活性去甲基代谢物，即醋酸诺-左旋甲丙氨酯，这进一步被去甲基化为第二种活性代谢物，即醋酸二诺-左旋甲丙氨酯。这些代谢物的效力超过了母药。 半衰期：2.6天

Levomethadyl acetate undergoes extensive first-pass metabolism to the active demethylated metabolite nor-levomethadyl acetate, which is further demethylated to a second active metabolite, dinor-levomethadyl acetate. These metabolites are more potent than the parent drug. Half Life: 2.6 days

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

阿片受体（穆、卡帕、德尔塔）与G蛋白受体偶联，并通过激活效应蛋白的G蛋白作为突触传递的正负调节因子。阿片类药物与受体的结合刺激G蛋白复合物上GTP与GDP的交换。由于效应器系统位于质膜内表面的腺苷酸环化酶和cAMP，阿片类药物通过抑制腺苷酸环化酶来降低细胞内cAMP。随后，抑制了如P物质、GABA、多巴胺、乙酰胆碱和去甲肾上腺素等疼痛相关神经递质的释放。阿片类药物还抑制vasopressin（血管加压素）、somatostatin（生长抑素）、insulin（胰岛素）和glucagon（胰高血糖素）的释放。左醋甲氢可有效地开放钙依赖性内向整流钾通道（OP1受体激动剂），导致超极化并减少神经元的兴奋性。

Opiate receptors (Mu, Kappa, Delta) are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Levomethadyl acetate effectively opens calcium-dependent inwardly rectifying potassium channels (OP1 receptor agonist), resulting in hyperpolarization and reduced neuronal excitability.

来源:Toxin and Toxin Target Database (T3DB)

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

医学问题可能包括肺充血、肝病、破伤风、心脏瓣膜感染、皮肤脓肿、贫血和肺炎。过量可能会导致死亡。

Medical problems can include congested lungs, liver disease, tetanus, infection of the heart valves, skin abscesses, anemia and pneumonia. Death can occur from overdose.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露途径

醋酸左美沙醇口服溶液可迅速吸收。

Levomethadyl acetate is rapidly absorbed from an oral solution.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 症状

过量迹象包括呼吸暂停、循环衰竭、肺水肿、心脏骤停和死亡。

Signs of overdose include apnea, circulatory collapse, pulmonary edema, cardiac arrest, and death.

来源:Toxin and Toxin Target Database (T3DB)

吸收、分配和排泄

• 吸收

醋酸左美沙醇口服溶液可迅速吸收。

Levomethadyl acetate is rapidly absorbed from an oral solution.

来源:DrugBank

安全信息

• 储存条件：
  库房应保持通风、低温和干燥的环境。

反应信息

• 作为反应物：
  描述：

  [(3S,6S)-6-二甲氨基-4,4-二苯基-庚烷-3-基]乙酸酯 在 镍 calcium sulfate 、 potassium permanganate 、 氢气 作用下， 以 水 、 溶剂黄146 、 叔丁醇 为溶剂， 生成 (-)-alpha-Dinoracetylmethadol
  参考文献：
  名称：

  Synthesis of a new metabolite of acetylmethadol

  摘要：

  The primary amine metabolites of alpha-(plus or minus)- alpha-(minus)-acetylmethadol were synthesized. A neutral permanganate oxidation of noracetylmethadol gave a nitroalkane. This unusual oxidation product was readily converted to the primary amine metabolite of acetylmethadol.

  DOI：

  10.1021/jm00237a010
• 作为产物：
  描述：

  乙酸酐 、 alkaline earth salt of/the/ methylsulfuric acid 在 吡啶 作用下， 生成 [(3S,6S)-6-二甲氨基-4,4-二苯基-庚烷-3-基]乙酸酯
  参考文献：
  名称：

  与陨石有关的旋光化合物。

  摘要：

  DOI：

  10.1021/ja01170a025

文献信息

• [EN] SPIROLACTAM CGRP RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DE RÉCEPTEUR DE CGRP À BASE DE SPIROLACTAME
  申请人：MERCK SHARP & DOHME

  公开号：WO2013169567A1

  公开（公告）日：2013-11-14

  The present invention is directed to spirolactam analogues which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

  本发明涉及螺内酰胺类似物，其为CGRP受体拮抗剂，可用于治疗或预防涉及CGRP的疾病，如偏头痛。该发明还涉及包含这些化合物的药物组合物，以及在预防或治疗涉及CGRP的这类疾病中使用这些化合物和组合物。
• [EN] IMIDAZOLINONE DERIVATIVES AS CGRP RECEPTOR ANTAGONISTS<br/>[FR] DÉRIVÉS D'IMIDAZOLINONE EN TANT QU'ANTAGONISTES DE RÉCEPTEURS CGRP
  申请人：MERCK SHARP & DOHME

  公开号：WO2010077752A1

  公开（公告）日：2010-07-08

  The present invention is directed to imidazolinone derivatives which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

  本发明涉及嘧啶啉酮衍生物，其为CGRP受体拮抗剂，可用于治疗或预防涉及CGRP的疾病，如偏头痛。该发明还涉及包含这些化合物的药物组合物，以及在预防或治疗涉及CGRP的这类疾病中使用这些化合物和组合物。
• [EN] PEPTIDE-BASED MULTIPLE-DRUG DELIVERY VEHICLE<br/>[FR] VÉHICULE D'ADMINISTRATION DE MÉDICAMENTS MULTIPLES À BASE DE PEPTIDES
  申请人：ARIEL-UNIVERSITY RES AND DEV COMPANY LTD

  公开号：WO2017068577A1

  公开（公告）日：2017-04-27

  A molecular structure comprising a targeting moiety, a multi-functional peptide platform and a plurality of controllably released bioactive agents attached thereto is provided herein.

  本文提供了一种包括靶向基团、多功能肽平台和附着在其上的多种可控释放的生物活性剂的分子结构。
• 3,4,6-Substituted pyridazines for treating neuropathic pain and associated syndromes
  申请人：Sultzbaugh Lance

  公开号：US20070191365A1

  公开（公告）日：2007-08-16

  The present invention is directed to the use of 3,4,6-substituted pyridazines such as those characterized by structure I for treating conditions such as neuropathic pain among others.

  本发明涉及使用3,4,6-取代吡啶嗪，如结构I所示的化合物，用于治疗神经病痛等疾病。
• [EN] QUATERNARY PIPERIDINE DERIVATIVES AND USES THEREOF<br/>[FR] DÉRIVÉS QUATERNAIRES DE PIPÉRIDINE ET LEURS UTILISATIONS
  申请人：ASTRAZENECA AB

  公开号：WO2010071575A1

  公开（公告）日：2010-06-24

  This invention generally relates to quaternary piperidine compounds, particularly substituted 3-phenylpiperidine compounds and salts thereof. This invention also relates to pharmaceutical compositions comprising such a compound, uses of such a compound (including, for example, treatment methods and medicament preparations), and processes for making such a compound.

  这项发明通常涉及四元哌啶化合物，特别是取代的3-苯基哌啶化合物及其盐。这项发明还涉及包括这种化合物的药物组合物、这种化合物的用途（包括治疗方法和药物制剂等），以及制备这种化合物的方法。