N-甲基-3,4-二羟基安非他命盐酸盐 | 15398-87-5

• 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: N-甲基-3,4-二羟基安非他命盐酸盐
• 英文名称: (+/-)-DHMA
• 英文别名: (R,S)-N-methyl-3,4-dihydroxyamphetamine；(+/-)-3,4-dihydroxymethamphetamine；N-methyl-α-methyldopamine；N-methyl-alpha-methyldopamine；3,4-dihydroxymethamphetamine；dihydroxymethamphetamine；4-[2-(methylamino)propyl]benzene-1,2-diol
• CAS: 15398-87-5
• 化学式: C₁₀H₁₅NO₂
• 分子量: 181.235
• InChiKey: NTCPGTZTPGFNOM-UHFFFAOYSA-N

物化性质

• 沸点：
  332.6±27.0 °C(Predicted)
• 密度：
  1.123±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  13
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  52.5
• 氢给体数：
  3
• 氢受体数：
  3

ADMET

代谢

N-甲基-3,4-二羟基苯丙胺是N-甲基-3,4-亚甲二氧基苯丙胺的人类已知代谢物。

N-Methyl-3,4dihydroxyamphetamine is a known human metabolite of N-methyl-3,4methylenedioxyamphetamine.

来源:NORMAN Suspect List Exchange

反应信息

• 作为反应物：
  描述：

  N-乙酰-L-半胱氨酸 、 N-甲基-3,4-二羟基安非他命盐酸盐 在 酪氨酸酶 作用下， 以 phosphate buffer 为溶剂， 反应 0.5h， 生成 5-(N-acetylcystein-S-yl)-N-methyl-α-methyldopamine
  参考文献：
  名称：

  Accumulation of Neurotoxic Thioether Metabolites of 3,4-(±)-Methylenedioxymethamphetamine in Rat Brain

  摘要：

  3,4-(±)-亚甲二氧基甲基苯丙胺（MDMA）的5-羟色胺能神经毒性似乎取决于全身代谢，因为直接将MDMA注入大脑无法再现其神经毒性。亚甲二氧基甲基苯丙胺会被去甲基化为儿茶酚代谢物 N -甲基-α-甲基多巴胺（N -Me-α-MeDA）。N -Me-α-MeDA的硫醚（谷胱甘肽和N -乙酰半胱氨酸）代谢物具有神经毒性，在大鼠脑中静脉注射MDMA后会出现这种代谢物。由于多剂量服用摇头丸是狂欢派对中的典型药物摄入方式，因此本研究旨在确定多剂量服用摇头丸对大鼠大脑中神经毒性硫醚代谢物浓度的影响。每隔 12 小时注射一次亚甲二氧基甲基苯丙胺（20 毫克/千克 s.c.），共注射四次，会导致纹状体透析液中 N -Me-α-MeDA 硫醚代谢物的显著积累。5-(glutathion- S -yl)- N -Me-α-MeDA 的 0-300 分钟曲线下面积（AUC）在第一次和第四次注射之间增加了 33%，而 2,5-双-(glutathion- S -yl)- N -Me-α-MeDA 的曲线下面积则增加了一倍。同样，5-( N -乙酰基半胱氨酸-S-基)-N-Me-α-MeDA（35%）和 2,5-双-( N -乙酰基半胱氨酸-S-基)-N-Me-α-MeDA（85%）的 AUC0-300 min 增加，反映了巯基酸代谢物的积累，这可能是因为它们的消除过程已达到饱和。事实上，5-(N-乙酰基 cystein- S-基)-N-Me-α-MeDA 和 2,5-双(N-乙酰基 cystein- S-基)-N-Me-α-MeDA 的消除半衰期在第一和第三剂量之间分别增加了 53% 和 28%。最后，虽然单硫醚共轭物的最大 C 值在每次注射后基本保持不变，但 2,5-双（谷胱甘肽-S-基）-N-Me-α-MeDA 和 2,5-双（N-乙酰基半胱氨酸-S-基）-N-Me-α-MeDA 的最大 C 值在第一次和第四次注射之间分别增加了 38% 和 ∼50%。这些数据表明，多次给药后，亚甲二氧基甲基苯丙胺的神经毒性代谢物可能会在大脑中积累。

  DOI：

  10.1124/jpet.107.128785
• 作为产物：
  描述：

  3,4-dimethoxymethamphetamine hydrochloride 在 氢溴酸 作用下， 生成 N-甲基-3,4-二羟基安非他命盐酸盐
  参考文献：
  名称：

  .alpha.-Methyldopamine derivatives. Synthesis and pharmacology

  摘要：

  DOI：

  10.1021/jm00250a012

文献信息

• Synthesis of Fatty Acid Amides of Catechol Metabolites that Exhibit Antiobesity Properties
  作者：Bruno Almeida、Jesús Joglar、María Jesús Luque Rojas、Juan Manuel Decara、Francisco Javier Bermúdez-Silva、Manuel Macias-González、Montserrat Fitó、Miguel Romero-Cuevas、Magí Farré、María Isabel Covas、Fernando Rodríguez de Fonseca、Rafael de la Torre

  DOI：10.1002/cmdc.201000161

  日期：——

  A series of fatty acid amides of 3,4‐methylenedioxymethamphetamine (MDMA) catechol metabolites were synthesized in order to evaluate their biological activities. Upon administration, all synthesized compounds resulted in negative modulation of food intake in rats. The most active compounds have affinity for the CB1 receptor and/or PPAR‐α; part of their biological activity may be caused by these double

  合成了一系列3,4-亚甲基二氧基甲基苯丙胺（MDMA）邻苯二酚代谢产物的脂肪酸酰胺，以评估其生物活性。给药后，所有合成的化合物均导致大鼠食物摄入的负调节。活性最高的化合物对CB 1受体和/或PPAR- α具有亲和力；它们的生物活性的一部分可能是由这些双重相互作用引起的。
• Serotonergic Neurotoxic Metabolites of Ecstasy Identified in Rat Brain
  作者：Douglas C. Jones、Christine Duvauchelle、Aiko Ikegami、Christopher M. Olsen、Serrine S. Lau、Rafael de la Torre、Terrence J. Monks

  DOI：10.1124/jpet.104.077628

  日期：2005.4

  The selective serotonergic neurotoxicity of 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) depends on their systemic metabolism. We have recently shown that inhibition of brain endothelial cell γ-glutamyl transpeptidase (γ-GT) potentiates the neurotoxicity of both MDMA and MDA, indicating that metabolites that are substrates for this enzyme contribute to the neurotoxicity. Consistent with this view, glutathione (GSH) and N -acetylcysteine conjugates of α-methyl dopamine (α-MeDA) are selective neurotoxicants. However, neurotoxic metabolites of MDMA or MDA have yet to be identified in brain. Using in vivo microdialysis coupled to liquid chromatography-tandem mass spectroscopy and a high-performance liquid chromatography-coulometric electrode array system, we now show that GSH and N -acetylcysteine conjugates of N -methyl-α-MeDA are present in the striatum of rats administered MDMA by subcutaneous injection. Moreover, inhibition of γ-GT with acivicin increases the concentration of GSH and N -acetylcysteine conjugates of N -methyl-α-MeDA in brain dialysate, and there is a direct correlation between the concentrations of metabolites in dialysate and the extent of neurotoxicity, measured by decreases in serotonin (5-HT) and 5-hydroxyindole acetic (5-HIAA) levels. Importantly, the effects of acivicin are independent of MDMA-induced hyperthermia, since acivicin-mediated potentiation of MDMA neurotoxicity occurs in the context of acivicin-mediated decreases in body temperature. Finally, we have synthesized 5-( N -acetylcystein- S -yl)- N -methyl-α-MeDA and established that it is a relatively potent serotonergic neurotoxicant. Together, the data support the contention that MDMA-mediated serotonergic neurotoxicity is mediated by the systemic formation of GSH and N -acetylcysteine conjugates of N -methyl-α-MeDA (and α-MeDA). The mechanisms by which such metabolites access the brain and produce selective serotonergic neurotoxicity remain to be determined.

  3,4-亚甲二氧基苯丙胺（MDA）和3,4-亚甲二氧基甲基苯丙胺（MDMA，摇头丸）的选择性血清素能神经毒性取决于它们的全身代谢。我们最近的研究表明，抑制脑内皮细胞的γ-谷氨酰转肽酶（γ-GT）会增强MDMA和MDA的神经毒性，这表明作为该酶底物的代谢物会导致神经毒性。与这一观点一致，谷胱甘肽（GSH）和α-甲基多巴胺（α-MeDA）的N-乙酰半胱氨酸共轭物是选择性神经毒剂。然而，尚未在大脑中发现亚甲二氧基甲基苯丙胺或 MDA 的神经毒性代谢物。通过使用体内微透析法、液相色谱-串联质谱法和高效液相色谱-库仑计电极阵列系统，我们发现在皮下注射 MDMA 的大鼠纹状体中存在 GSH 和 N - 乙酰半胱氨酸共轭物 N - 甲基-α-MeDA。此外，用阿西维辛抑制γ-GT会增加脑透析液中GSH和N-甲基-α-MeDA的N-乙酰半胱氨酸共轭物的浓度，而且透析液中代谢物的浓度与神经毒性程度直接相关，神经毒性程度通过血清素（5-HT）和5-羟基吲哚乙酸（5-HIAA）水平的下降来衡量。重要的是，阿西维辛的作用与MDMA诱导的高热无关，因为阿西维辛介导的MDMA神经毒性增效是在阿西维辛介导的体温下降的背景下发生的。最后，我们合成了 5-( N -acetylcystein- S -yl)- N -methyl-α-MeDA 并确定它是一种相对强效的血清素能神经毒剂。总之，这些数据支持以下论点，即亚甲二氧基甲基苯丙胺介导的血清素能神经毒性是由 N -甲基-α-MeDA（和 α-MeDA）的 GSH 和 N -乙酰半胱氨酸共轭物的全身性形成介导的。这些代谢物进入大脑并产生选择性血清素能神经毒性的机制仍有待确定。
• Ecstasy-class derivatives, immunogens, and antibodies and their use in detecting ecstasy-class drugs
  申请人：Roche Diagnostics GmbH

  公开号：EP1498415B1

  公开（公告）日：2007-06-27
• Metabolic Regio- and Stereoselectivity of Cytochrome P450 2D6 towards 3,4-Methylenedioxy-<i>N</i>-alkylamphetamines:  in Silico Predictions and Experimental Validation
  作者：Peter H. J. Keizers、Chris de Graaf、Frans J. J. de Kanter、Chris Oostenbrink、K. Anton Feenstra、Jan N. M. Commandeur、Nico P. E. Vermeulen

  DOI：10.1021/jm050338+

  日期：2005.9.1

  A series of 3,4-methylenedioxy-N-alkylamphetamines (MDAAs) were automatically docked and subjected to molecular dynamics (MD) simulations in a cytochrome P450 2D6 (CYP2D6) protein model. The predicted substrate binding orientations, sites of oxidation, and relative reactivities were compared to the experimental data of wild-type and Phe(120)Ala mutant CYP2D6. Automated docking results were not sufficient to accurately rationalize experimental binding orientations of 3,4-methylenedioxy-N-methylamphetamine (MDMA) in the two enzymes as measured with spin lattice relaxation NMR. Nevertheless, the docking results could be used as starting structures for MD simulations. Predicted binding orientations of MDMA and sites of oxidation of the MDAAs derived from MD simulations matched well with the experimental data. It appeared the experimental results were best described in MD simulations considering the nitrogen atoms of the MDAAs in neutral form. Differences in regioselectivity and stereoselectivity in the oxidative metabolism of the MDAAs by the Phe(120)Ala mutant CYP2D6 were correctly predicted, and the effects of the Phe(120)Ala mutation could be rationalized as well.
• Identification of the human cytochromes P450 involved in the oxidative metabolism of “Ecstasy”-related designer drugs
  作者：Klaus-Peter Kreth、Karl-Artur Kovar、Matthias Schwab、Ulrich M Zanger

  DOI：10.1016/s0006-2952(00)00284-7

  日期：2000.6

  The human cytochrome P450 (CYP) isozymes catalyzing the oxidative metabolism of the widely abused amphetamine derivatives MDMA (N-methyl-3,4-mechylenedioxyamphetamine, "Ecstasy"), MDE (Nethyl-3,4-methylenedioxyampheramine, "Eve"), and MDA (3,4-mechylenedioxyamphetamine) were identified. Using a simplified non-extractive reversed-phase HPLC assay with fluorescence detection, biphasic Michaelis-Menten kinetics were obtained for formation of all three dihydroxyamphetamines in liver microsomes from a CYP2D6 extensive metabolizer subject. In contrast, no low K-m component was detectable in microsomes from a poor metabolizer subject. Additional specific probes for CYP2D6 further confirmed this isozyme as the exclusive low K-m component for demethylenation. P450-selective inhibitors applied to CYP2D6-inhibited microsomes and activity measurements in a series of recombinant P450s suggested CYP1A2 as the major high K-m component with contributions by CYP2B6 and CYP3A4. Moreover, the relative CYP1A2 content of a panel of 12 human livers was weakly but significantly correlated to the high K-m demethylenase activity (Spearman rank correlation coefficient [r(s)] = 0.58; P < 0.05). Microsomal maximal velocities for N-dealkylation were at least 7-fold lower than for demethylenation and were characterized by apparently monophasic kinetics. The most important isozyme for this reaction appeared to be CYP2B6, the microsomal content of which was found to be strongly correlated to N-deethylation of MDE (r(s) = 0.90; P < 0.001). We conclude that, in addition to CP2D6 as the sole high-affinity demethylenase, several other P450 isozymes have the capacity to contribute to microsomal oxidative metabolism of methylenedioxyamphetamines. This may be of particular importance in individuals genetically lacking functional CYP2D6. (C) 2000 Elsevier Science Inc.