2-亚乙基-1,5-二甲基-3,3-二苯基吡咯烷高氯酸盐 | 30223-73-5

• 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: 2-亚乙基-1,5-二甲基-3,3-二苯基吡咯烷高氯酸盐
• 英文名称: 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine
• 英文别名: EDDP；Pyrrolidine, 1,5-dimethyl-3,3-diphenyl-2-ethylidene-
• CAS: 30223-73-5
• 化学式: C₂₀H₂₃N
• 分子量: 277.409
• InChiKey: AJRJPORIQGYFMT-UHFFFAOYSA-N

物化性质

• 沸点：
  130 °C(Press: 0.1 Torr)
• 密度：
  1.051±0.06 g/cm3(Predicted)
• 溶解度：
  乙腈（微溶）、氯仿（微溶）、甲醇（微溶）

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  3.2
• 氢给体数：
  0
• 氢受体数：
  1

安全信息

• 危险等级：
  5.1
• 安全说明：
  S22,S24/25
• WGK Germany：
  3
• 包装等级：
  III
• 危险类别：
  5.1
• 危险品运输编号：
  UN 1479

反应信息

• 作为产物：
  描述：

  美沙酮 在 potassium phosphate buffer 、 P₄₅₀ 3A₄ cytochrome 作用下， 以 水 为溶剂， 反应 0.33h， 生成 2-亚乙基-1,5-二甲基-3,3-二苯基吡咯烷高氯酸盐
  参考文献：
  名称：

  细胞色素P450 3A4酶参与人肝微粒体中美沙酮的N-去甲基化。

  摘要：

  美沙酮已成为用于鸦片依赖性治疗的最广泛使用的药物之一。该药物在人体中被细胞色素P450肝酶家族广泛代谢，产生N-去甲基化代谢产物，该代谢产物自发环化为2，1-亚乙基-1，5-二甲基-3，3-二苯基吡咯烷。在一组由20种人类肝脏微粒体制剂制成的面板中，检查了参与该氧化N-脱甲基化反应的细胞色素P450的具体形式，这些制剂先前已对其P450酶含量进行了表征。美沙酮以545 +/- 258 microM（n = 3）的表观Km脱甲基。代谢速率为745 +/- 574 pmol /（最小毫克蛋白质）。该代谢途径与雌二醇2-羟基化，睾丸激素6β-羟基化，硝苯地平氧化，红霉素N-去甲基化和托瑞米芬N-去甲基化密切相关，P450 3A4支持所有这些单加氧酶活性。此外，使用单克隆抗人P450 3A4抗体通过免疫定量测定的肝微粒体样品的总P450 3A含量与美沙酮去甲基化相关（r = 0.72； p <0.

  DOI：

  10.1021/tx950116m

文献信息

• An in vitro approach to potential methadone metabolic-inhibition interactions
  作者：Stephanie Bomsien、Gisela Skopp

  DOI：10.1007/s00228-007-0327-z

  日期：2007.8.8

  Objective The aim of this study was to assess the drug interaction potential of psychotropic medication on methadone N-demethylation using cDNA-expressed cytochrome P450 CYP enzymes.Methods Methadone was incubated with various drugs (n=10) and cDNA-expressed CYP3A4, CYP2D6, CYP2B6, CYP2C19 and CYP1A2 enzymes to screen for their inhibition potency. The nature of enzyme selective activity for inhibition was further investigated for potent inhibitors. To test for a mechanism-based component in inhibition, all substances were tested with preincubation and without. 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) concentration was determined by liquid chromatography/tandem mass spectrometry following liquid/liquid extraction.ResultsFormation of EDDP was catalysed by CYP3A4, CYP2D6 and CYP2C19. The N-demethylation of methadone was preferentially inhibited by amitriptyline, buprenorphine, methylenedioxymethamphetamine (MDMA) and zolpidem. Both amitriptyline and buprenorphine were strong, reversible inhibitors of CYP3A4. Similarly, amitriptyline and MDMA were identified as inhibitors of CYP2D6. Zolpidem revealed a mechanism-based inhibition of CYP3A4.Conclusion Amitriptyline, MDMA and zolpidem are likely to slow down conversion of methadone and to increase its area under the curve (AUC). A consideration of the in vitro evidence of drug-methadone interactions should help to improve patient care during methadone maintenance treatment.
• Methadone metabolism by human placenta
  作者：Tatiana N. Nanovskaya、Sujal V. Deshmukh、Ilona A. Nekhayeva、Olga L. Zharikova、Gary D.V. Hankins、Mahmoud S. Ahmed

  DOI：10.1016/j.bcp.2004.04.011

  日期：2004.8

  Methadone pharmacotherapy is considered the standard for treatment of the pregnant heroin/opioid addict. One of the factors affecting the transfer kinetics of opioids across human placenta and their levels in the fetal circulation is their metabolism by the tissue. The aim of this investigation is to identify the enzyme(s) responsible for the metabolism of methadone, determine the kinetics of the reaction and the metabolites formed utilizing placental tissue obtained from term healthy pregnancies. Microsomal fractions of trophoblast tissue homogenates had the highest activity in catalyzing the metabolism of methadone. The product formed was identified by HPLC-UV as 2ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). Inhibitors selective for cytochrome P450 (CYP) isozymes were used to identify the enzyme catalyzing the biotransformation of methadone. Aminoglutethimide and 4-hydroxyandrostenedione inhibited EDDP formation by 88 and 70%, respectively, suggesting that CYP19/aromatase is the enzyme catalyzing the reaction. This was confirmed by the effect of monoclonal antibodies raised against CYP19 that caused an 80% inhibition of the reaction. The apparent K-m and V-max values for the CYP19 catalyzed metabolism of methadone to EDDP were 424 +/- 92 muM and 420 +/- 89 mumol (mg protein)(-1) min(-1), respectively. Kinetic analysis of a cDNA-expressed CYP19 for the metabolism of methadone to EDDP was identical to that by placental microsomes. Taken together, these data indicate that CYP19/aromatase is the major enzyme responsible for the metabolism of methadone to EDDP in term human placentas obtained from healthy pregnancies. (C) 2004 Elsevier Inc. All rights reserved.
• Involvement of Cytochrome P450 3A4 Enzyme in the <i>N</i>-Demethylation of Methadone in Human Liver Microsomes
  作者：Christelle Iribarne、François Berthou、Susan Baird、Yvonne Dréano、Daniel Picart、Jean Pierre Bail、Philippe Beaune、Jean François Ménez

  DOI：10.1021/tx950116m

  日期：1996.1.1

  metabolized by the cytochrome P450 hepatic enzyme family in man, yielding an N-demethylated metabolite that cyclizes spontaneously into 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine. The specific forms of cytochrome P450 involved in this oxidative N-demethylation were examined in a panel of 20 human liver microsomal preparations previously characterized with respect to their P450 enzyme contents. Methadone

  美沙酮已成为用于鸦片依赖性治疗的最广泛使用的药物之一。该药物在人体中被细胞色素P450肝酶家族广泛代谢，产生N-去甲基化代谢产物，该代谢产物自发环化为2，1-亚乙基-1，5-二甲基-3，3-二苯基吡咯烷。在一组由20种人类肝脏微粒体制剂制成的面板中，检查了参与该氧化N-脱甲基化反应的细胞色素P450的具体形式，这些制剂先前已对其P450酶含量进行了表征。美沙酮以545 +/- 258 microM（n = 3）的表观Km脱甲基。代谢速率为745 +/- 574 pmol /（最小毫克蛋白质）。该代谢途径与雌二醇2-羟基化，睾丸激素6β-羟基化，硝苯地平氧化，红霉素N-去甲基化和托瑞米芬N-去甲基化密切相关，P450 3A4支持所有这些单加氧酶活性。此外，使用单克隆抗人P450 3A4抗体通过免疫定量测定的肝微粒体样品的总P450 3A含量与美沙酮去甲基化相关（r = 0.72； p <0.