(+)-(E)-10-Hydroxy-Amitriptyline | 129312-49-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 二苯并环庚烯
• 英文名称: (+)-(E)-10-Hydroxy-Amitriptyline
• 英文别名: (-)-(E)-10-Hydroxy-Amitriptylline；(2E)-2-[3-(dimethylamino)propylidene]tricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-9-ol
• CAS: 129312-49-8
• 化学式: C₂₀H₂₃NO
• 分子量: 293.409
• InChiKey: GHWBJXOKAFHZAI-SFQUDFHCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  23.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (+)-(E)-10-Hydroxy-Amitriptyline 在 CYP₂C₁₉ 作用下， 生成 反式-10-羟基去甲替林
  参考文献：
  名称：

  血清样品中醌类化合物的推导同时测定阿米替林和去甲替林的新方法

  摘要：

  通过磁性固相萃取（MSPE）和分光光度法联合测定两种三环抗抑郁药（TCA）[阿米替林（AT）及其主要代谢物（去甲替林； NT）]的新颖有效策略建议。为此，使用咪唑鎓离子液体（Imz）改性的Fe 3 O 4 @SiO 2纳米颗粒（Fe 3 O 4 @SiO 2-Imz）用作MSPE的吸附剂。在优化条件下进行了预浓缩（负载-解吸）研究，包括pH，吸附剂量，接触时间，洗脱液体积和解吸时间。之后，通过特定策略确定每种药物。乙醛（AC）和2,3,5,6-四氯-1,4-苯醌（氯腈; CL）用作与NT反应的化学试剂，而AT不与这些试剂反应。该方法基于NT的仲胺基和AC之间的缩合反应，得到烯胺，随后与CL反应，生成氯化醌取代的烯胺。最终产物在556 nm处显示出最大吸收，而AT在240 nm处测定。血清样品中NT和AT的检出限（LOD）为0.19和0。− 1。NT和AT的定量限（LOQs）分别为0.63和2

  DOI：

  10.1016/j.saa.2016.06.013
• 作为产物：
  描述：

  阿米替林 在 cDNA-expressed human cytochrome P₄₅₀ (CYP) 2D₆ enzyme 作用下， 以 水 为溶剂， 反应 0.25h， 生成 (+)-(E)-10-Hydroxy-Amitriptyline
  参考文献：
  名称：

  Metabolism of the Tricyclic Antidepressant Amitriptyline by cDNA-Expressed Human Cytochrome P450 Enzymes

  摘要：

  The metabolism of amitriptyline was studied in vitro using cDNA-expressed human cytochrome P450 (CYP) enzymes 1A2, 3A4, 2C9, 2C19, 2D6 and 2E1. CYP 2C19 was the most important enzyme with regard to the demethylation of amitriptyline, the quantitatively most important metabolic pathway. CYP 1A2, 3A4, 2C9 and CYP 2D6 also participated in the demethylation of amitriptyline. CYP 2D6 was the sole enzyme mediating the hydroxylation of amitriptyline, and (E)10-OH-amitriptyline was exclusively produced. CYP 2E1 did not metabolize amitriptyline. Concerning the quantitative relations, CYP 2C19 and 2D6 exhibited high affinities with K-m values in the range of 5-13 mu mol/l, whereas the affinities of 1A2, 3A4 and 2C9 were somewhat lower with K, values ranging from 74 to 92 mu mol/l. CYP 2C19 displayed the highest reaction capacity per mole with V-max equal to 475 mol h(-1) (mol CYP)(-1). The other enzymes had V-max values in the range of 90-145 mol h(-1) (mol CYP)(-1). Allowing for the typical relative distribution of amounts of CYP enzymes in the liver, a simulation study suggested that, at therapeutic doses, on average about 60% of the metabolism depended on CYP 2C19. At toxic doses, CYP 2C19 is expected to be saturated, and CYP 3A4 may now play a dominant role in the metabolism.

  DOI：

  10.1159/000139533

文献信息

• Regioselectivity and Substrate Concentration-dependency of Involvement of the CYP2D Subfamily in Oxidative Metabolism of Amitriptyline and Nortriptyline in Rat Liver Microsomes
  作者：Yasuhiro Masubuchi、Takashi Iwasa、Shoichi Fujita、Tokuji Suzuki、Toshiharu Horie、Shizuo Narimatsu

  DOI：10.1111/j.2042-7158.1996.tb06003.x

  日期：2011.4.12

  Kinetic analysis of the metabolism of amitriptyline and nortriptyline using liver microsomes from Wistar rats showed that more than one enzyme was involved in each reaction except for monophasic amitriptyline N-demethylation. The Vmax values particularly in the high-affinity sites for E-10-hydroxylation of both drugs were larger than those for Z-10-hydroxylations. Their E- and Z-10-hydroxylase activities in Dark-Agouti rats, which are deficient for CYP2D1, were significantly lower than those in Wistar rats at a lower substrate concentration (5 μM). The strain difference was reduced at a higher substrate concentration (500 μM). A similar but a smaller strain difference was also observed in nortriptyline N-demethylase activity, and a pronounced sex difference (male > female) was observed in N-demethylation of both drugs in Wistar and Dark-Agouti rats. The reactions with the strain difference were inhibited concentration-dependently by sparteine, a substrate of the CYP2D subfamily, and an antibody against a CYP2D isoenzyme. The profiles of these decreased metabolic activities corresponded to that of the lower metabolic activities in Dark-Agouti rats.

  These results indicated that a cytochrome P450 isozyme in the CYP2D subfamily was involved in E- and Z- 10-hydroxylations of amitriptyline and nortriptyline in rat liver microsomes as a major isozyme in a low substrate concentration range. It seems likely that the CYP2D enzyme contributes to nortriptyline N-demethylation.

  摘要：对Wistar大鼠肝微粒体中阿米替林和诺替林代谢的动力学分析表明，除了单相阿米替林N-去甲基化反应外，每个反应中涉及多种酶。尤其是在高亲和位点上，两种药物的E-10-羟基化的Vmax值比Z-10-羟基化的要大。在缺乏CYP2D1的Dark-Agouti大鼠中，这两种药物的E-和Z-10-羟化活性在较低底物浓度（5 μM）下明显低于Wistar大鼠。在较高底物浓度（500 μM）下，品系差异减小。在诺替林N-去甲基酶活性中也观察到类似但较小的品系差异，而在Wistar和Dark-Agouti大鼠中，两种药物的N-去甲基化反应中观察到明显的性别差异（男性>女性）。具有品系差异的反应受到CYP2D亚家族底物斯帕替因和抗CYP2D同工酶抗体的浓度依赖性抑制。这些降低的代谢活性的特征与Dark-Agouti大鼠中较低的代谢活性相符。 这些结果表明，在低底物浓度范围内，CYP2D亚家族的一种细胞色素P450同工酶参与了大鼠肝微粒体中阿米替林和诺替林的E-和Z-10-羟基化作用，作为一个主要同工酶。CYP2D酶可能有助于诺替林N-去甲基化。
• Synthesis and NMR Studies of Z- and E-Isomers of 10-Oxo and 10-Hydroxy Derivatives of Amitriptyline and Nortriptyline.
  作者：Niels Lassen、Jens Perregaard、Toshiaki Nishida、Curt R. Enzell、Jan-Eric Berg、Thomas W. Dingle、Richard Vaughan Williams、Ramanathan Mahedevan

  DOI：10.3891/acta.chem.scand.37b-0335

  日期：——
• LASSEN, N.;PERREGAARD, J., ACTA CHEM. SCAND., 1983, 37, N 4, 335-340
  作者：LASSEN, N.、PERREGAARD, J.

  DOI：——

  日期：——
• A novel strategy for spectrophotometric simultaneous determination of amitriptyline and nortriptyline based on derivation with a quinonoid compound in serum samples
  作者：Amir Farnoudian-Habibi、Bakhshali Massoumi、Mehdi Jaymand

  DOI：10.1016/j.saa.2016.06.013

  日期：2016.11

  strategy. Acetaldehyde (AC), and 2,3,5,6-tetrachloro-1,4-benzoquinone (chloranil; CL) were used as chemical reagents for reaction with NT, while AT did not react with these reagents. This method is based on the condensation reaction between secondary amine group of NT and AC to afford an enamine, and subsequently reaction with CL to produce a chlorinated quinone-substituted enamine. The final product exhibited

  通过磁性固相萃取（MSPE）和分光光度法联合测定两种三环抗抑郁药（TCA）[阿米替林（AT）及其主要代谢物（去甲替林； NT）]的新颖有效策略建议。为此，使用咪唑鎓离子液体（Imz）改性的Fe 3 O 4 @SiO 2纳米颗粒（Fe 3 O 4 @SiO 2-Imz）用作MSPE的吸附剂。在优化条件下进行了预浓缩（负载-解吸）研究，包括pH，吸附剂量，接触时间，洗脱液体积和解吸时间。之后，通过特定策略确定每种药物。乙醛（AC）和2,3,5,6-四氯-1,4-苯醌（氯腈; CL）用作与NT反应的化学试剂，而AT不与这些试剂反应。该方法基于NT的仲胺基和AC之间的缩合反应，得到烯胺，随后与CL反应，生成氯化醌取代的烯胺。最终产物在556 nm处显示出最大吸收，而AT在240 nm处测定。血清样品中NT和AT的检出限（LOD）为0.19和0。− 1。NT和AT的定量限（LOQs）分别为0.63和2
• Metabolism of the Tricyclic Antidepressant Amitriptyline by cDNA-Expressed Human Cytochrome P450 Enzymes
  作者：Ole V. Olesen、Kristian Linnet

  DOI：10.1159/000139533

  日期：——

  The metabolism of amitriptyline was studied in vitro using cDNA-expressed human cytochrome P450 (CYP) enzymes 1A2, 3A4, 2C9, 2C19, 2D6 and 2E1. CYP 2C19 was the most important enzyme with regard to the demethylation of amitriptyline, the quantitatively most important metabolic pathway. CYP 1A2, 3A4, 2C9 and CYP 2D6 also participated in the demethylation of amitriptyline. CYP 2D6 was the sole enzyme mediating the hydroxylation of amitriptyline, and (E)10-OH-amitriptyline was exclusively produced. CYP 2E1 did not metabolize amitriptyline. Concerning the quantitative relations, CYP 2C19 and 2D6 exhibited high affinities with K-m values in the range of 5-13 mu mol/l, whereas the affinities of 1A2, 3A4 and 2C9 were somewhat lower with K, values ranging from 74 to 92 mu mol/l. CYP 2C19 displayed the highest reaction capacity per mole with V-max equal to 475 mol h(-1) (mol CYP)(-1). The other enzymes had V-max values in the range of 90-145 mol h(-1) (mol CYP)(-1). Allowing for the typical relative distribution of amounts of CYP enzymes in the liver, a simulation study suggested that, at therapeutic doses, on average about 60% of the metabolism depended on CYP 2C19. At toxic doses, CYP 2C19 is expected to be saturated, and CYP 3A4 may now play a dominant role in the metabolism.