4-羟基-3-甲氧基甲基苯丙胺盐酸盐 | 438625-58-2

• 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: 4-羟基-3-甲氧基甲基苯丙胺盐酸盐
• 英文名称: (+/-)-4-Hydroxy-3-methoxymethamphetamine hydrochloride
• 英文别名: 4-Hydroxy-3-methoxy Methamphetamine Hydrochloride；2-methoxy-4-[2-(methylamino)propyl]phenol;hydrochloride
• CAS: 438625-58-2
• 化学式: C₁₁H₁₇NO₂*ClH
• 分子量: 231.722
• InChiKey: LDRJCJMDWCULLX-UHFFFAOYSA-N

物化性质

• 溶解度：
  DMF：30mg/mL； DMSO：30mg/mL；乙醇：30mg/mL； PBS（pH 7.2）：10 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  1.97
• 重原子数：
  15
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  41.5
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  uridine 5'-diphosphoglucuronic acid 、 4-羟基-3-甲氧基甲基苯丙胺盐酸盐 在 alamethicin 作用下， 反应 20.0h， 以71%的产率得到HMMA glucuronide
  参考文献：
  名称：

  4-Hydroxy-3-methoxymethamphetamine Glucuronide as a Phase II Metabolite of 3,4-Methylenedioxymethamphetamine: Enzyme-Assisted Synthesis and Involvement of Human Hepatic Uridine 5'-Diphosphate-Glucuronosyltransferase 2B15 in the Glucuronidation

  摘要：

  3,4-亚甲二氧基甲基苯丙胺（MDMA）是最流行的非法娱乐药物之一，主要通过药物代谢酶代谢为 4-羟基-3-甲氧基甲基苯丙胺（HMMA）。HMMA 经第二阶段酶进一步代谢，生成葡萄糖醛酸苷或硫酸盐，排入尿液。在本研究中，对各种微粒体进行的酶动力学研究表明，用 Aroclor 1254 预处理的大鼠肝脏微粒体最适合在酶辅助下合成葡萄糖醛酸（HMMA-Gluc）。这种方法可选择性地生成 HMMA-Gluc 的 β-异构体，分离产率非常高（71%），纯度足以用于分析亚甲二氧基甲基苯丙胺摄入量和酶动力学研究。我们还通过 LC-MS 方法鉴定了催化 HMMA 葡萄糖醛酸化的人类尿苷-5′-二磷酸-葡萄糖醛酸基转移酶（UGT）同工酶。在昆虫细胞中表达的 12 种人重组 UGT 同工酶中，UGT2B15 是唯一在催化 HMMA 葡萄糖醛酸化过程中表现出足够酶活性的同工酶，其 Km 和 Vmax 值分别为 3.8 mM 和 1.6 nmol/min/mg。UGT2B15能够进行HMMA葡萄糖醛酸化反应的发现表明，这种同工酶形式可能在人体MDMA代谢中发挥重要作用。

  DOI：

  10.1248/cpb.57.472
• 作为产物：
  描述：

  4-羟基-3-甲氧基苯丙酮 、 盐酸甲胺 在 盐酸 、 sodium cyanoborohydride 作用下， 以 甲醇 为溶剂， 反应 51.5h， 以24%的产率得到4-羟基-3-甲氧基甲基苯丙胺盐酸盐
  参考文献：
  名称：

  Comparative potencies of 3,4-methylenedioxymethamphetamine (MDMA) analogues as inhibitors of [³ H]noradrenaline and [³ H]5-HT transport in mammalian cell lines

  摘要：

  Background and purpose:Illegal ‘ecstasy’ tablets frequently contain 3,4‐methylenedioxymethamphetamine (MDMA)‐like compounds of unknown pharmacological activity. Since monoamine transporters are one of the primary targets of MDMA action in the brain, a number of MDMA analogues have been tested for their ability to inhibit [3H]noradrenaline uptake into rat PC12 cells expressing the noradrenaline transporter (NET) and [3H]5‐HT uptake into HEK293 cells stably transfected with the 5‐HT transporter (SERT).Experimental approach:Concentration–response curves for the following compounds at both NET and SERT were determined under saturating substrate conditions: 4‐hydroxy‐3‐methoxyamphetamine (HMA), 4‐hydroxy‐3‐methoxymethamphetamine (HMMA), 3,4‐methylenedioxy‐N‐hydroxyamphetamine (MDOH), 2,5‐dimethoxy‐4‐bromophenylethylamine (2CB), 3,4‐dimethoxymethamphetamine (DMMA), 3,4‐methylenedioxyphenyl‐2‐butanamine (BDB), 3,4‐methylenedioxyphenyl‐N‐methyl‐2‐butanamine (MBDB) and 2,3‐methylenedioxymethamphetamine (2,3‐MDMA).Key results:2,3‐MDMA was significantly less potent than MDMA at SERT, but equipotent with MDMA at NET. 2CB and BDB were both significantly less potent than MDMA at NET, but equipotent with MDMA at SERT. MBDB, DMMA, MDOH and the MDMA metabolites HMA and HMMA, were all significantly less potent than MDMA at both NET and SERT.Conclusions and implications:This study provides an important insight into the structural requirements of MDMA analogue affinity at both NET and SERT. It is anticipated that these results will facilitate understanding of the likely pharmacological actions of structural analogues of MDMA.British Journal of Pharmacology (2007) 152, 1121–1130; doi:10.1038/sj.bjp.0707473; published online 24 September 2007

  DOI：

  10.1038/sj.bjp.0707473

文献信息

• Synthesis and capillary electrophoretic analysis of enantiomerically enriched reference standards of MDMA and its main metabolites
  作者：Nieves Pizarro、Rafael de la Torre、Magı́ Farré、Jordi Segura、Amadeu Llebaria、Jesús Joglar

  DOI：10.1016/s0968-0896(01)00367-4

  日期：2002.4

  Enantiomerically-enriched (S)-3,4-methylenedioxymethamphetamine (MDMA) and its main metabolites (S)-4-hydroxy-3-methoxymethamphetamine (HMMA) and (S)-3,4-dihydroxymethamphetamine (HHMA) were prepared for unequivocal identification of the differential enantioselective metabolism of these compounds as well as for its application in the analysis of biological samples. Capillary electrophoresis with cyclodextrin derivatives and a chemical correlation of (S)-MDMA. (S)-HMMA and (S)-HHMA has been performed to assign the absolute stereochemistry of major isomers in analytical standards enriched with such enantiomers. (C) 2002 Elsevier Science Ltd. All rights reserved.
• Comparative potencies of 3,4-methylenedioxymethamphetamine (MDMA) analogues as inhibitors of [³ H]noradrenaline and [³ H]5-HT transport in mammalian cell lines
  作者：T Montgomery、C Buon、S Eibauer、P J Guiry、A K Keenan、G J McBean

  DOI：10.1038/sj.bjp.0707473

  日期：2007.12

  Background and purpose:Illegal ‘ecstasy’ tablets frequently contain 3,4‐methylenedioxymethamphetamine (MDMA)‐like compounds of unknown pharmacological activity. Since monoamine transporters are one of the primary targets of MDMA action in the brain, a number of MDMA analogues have been tested for their ability to inhibit [3H]noradrenaline uptake into rat PC12 cells expressing the noradrenaline transporter (NET) and [3H]5‐HT uptake into HEK293 cells stably transfected with the 5‐HT transporter (SERT).Experimental approach:Concentration–response curves for the following compounds at both NET and SERT were determined under saturating substrate conditions: 4‐hydroxy‐3‐methoxyamphetamine (HMA), 4‐hydroxy‐3‐methoxymethamphetamine (HMMA), 3,4‐methylenedioxy‐N‐hydroxyamphetamine (MDOH), 2,5‐dimethoxy‐4‐bromophenylethylamine (2CB), 3,4‐dimethoxymethamphetamine (DMMA), 3,4‐methylenedioxyphenyl‐2‐butanamine (BDB), 3,4‐methylenedioxyphenyl‐N‐methyl‐2‐butanamine (MBDB) and 2,3‐methylenedioxymethamphetamine (2,3‐MDMA).Key results:2,3‐MDMA was significantly less potent than MDMA at SERT, but equipotent with MDMA at NET. 2CB and BDB were both significantly less potent than MDMA at NET, but equipotent with MDMA at SERT. MBDB, DMMA, MDOH and the MDMA metabolites HMA and HMMA, were all significantly less potent than MDMA at both NET and SERT.Conclusions and implications:This study provides an important insight into the structural requirements of MDMA analogue affinity at both NET and SERT. It is anticipated that these results will facilitate understanding of the likely pharmacological actions of structural analogues of MDMA.British Journal of Pharmacology (2007) 152, 1121–1130; doi:10.1038/sj.bjp.0707473; published online 24 September 2007
• 4-Hydroxy-3-methoxymethamphetamine Glucuronide as a Phase II Metabolite of 3,4-Methylenedioxymethamphetamine: Enzyme-Assisted Synthesis and Involvement of Human Hepatic Uridine 5'-Diphosphate-Glucuronosyltransferase 2B15 in the Glucuronidation
  作者：Takuji Shoda、Kiyoshi Fukuhara、Yukihiro Goda、Haruhiro Okuda

  DOI：10.1248/cpb.57.472

  日期：——

  3,4-Methylenedioxymethamphetamine (MDMA), one of the most popular illicit recreational drugs, is metabolized primarily into 4-hydroxy-3-methoxymethamphetamine (HMMA) by drug-metabolizing enzymes. HMMA is further metabolized by phase II enzymes to give the glucuronide or sulfate which is excreted into urine. In the present study, enzyme kinetic studies with various microsomes showed that rat liver microsomes pretreated with Aroclor 1254 were most suitable for the enzyme-assisted synthesis of the glucuronide (HMMA-Gluc). This method selectively produced the β-anomer of HMMA-Gluc in a very high, isolated yield (71%), and with a purity that was sufficient for use in an analysis of MDMA intake and for enzyme kinetic studies. We also identified, by an LC-MS method, the human uridine 5′-diphosphate-glucuronosyltransferase (UGT) isoforms that catalyze the glucuronidation of HMMA. Among 12 isoforms of human recombinant UGT expressed in insect cells, UGT2B15 was the only isoform that showed adequate enzymatic activity in catalyzing HMMA glucuronidation with Km and Vmax values of 3.8 mM and 1.6 nmol/min/mg protein, respectively. The finding that UGT2B15 is capable of HMMA glucuronidation suggests this isoform may have an important in vivo role in human MDMA metabolism.

  3,4-亚甲二氧基甲基苯丙胺（MDMA）是最流行的非法娱乐药物之一，主要通过药物代谢酶代谢为 4-羟基-3-甲氧基甲基苯丙胺（HMMA）。HMMA 经第二阶段酶进一步代谢，生成葡萄糖醛酸苷或硫酸盐，排入尿液。在本研究中，对各种微粒体进行的酶动力学研究表明，用 Aroclor 1254 预处理的大鼠肝脏微粒体最适合在酶辅助下合成葡萄糖醛酸（HMMA-Gluc）。这种方法可选择性地生成 HMMA-Gluc 的 β-异构体，分离产率非常高（71%），纯度足以用于分析亚甲二氧基甲基苯丙胺摄入量和酶动力学研究。我们还通过 LC-MS 方法鉴定了催化 HMMA 葡萄糖醛酸化的人类尿苷-5′-二磷酸-葡萄糖醛酸基转移酶（UGT）同工酶。在昆虫细胞中表达的 12 种人重组 UGT 同工酶中，UGT2B15 是唯一在催化 HMMA 葡萄糖醛酸化过程中表现出足够酶活性的同工酶，其 Km 和 Vmax 值分别为 3.8 mM 和 1.6 nmol/min/mg。UGT2B15能够进行HMMA葡萄糖醛酸化反应的发现表明，这种同工酶形式可能在人体MDMA代谢中发挥重要作用。