(R)-N-Hydroxy-Methylenedioxymethamphetamine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并间二氧杂环戊烯类
• 英文名称: (R)-N-Hydroxy-Methylenedioxymethamphetamine
• 英文别名: N-[(2R)-1-(1,3-benzodioxol-5-yl)propan-2-yl]-N-methylhydroxylamine
• 化学式: C₁₁H₁₅NO₃
• 分子量: 209.245
• InChiKey: ORADFQZOLNHWRQ-MRVPVSSYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  41.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  (-)-3,4-Methylenedioxymethamphetamine 在 cytochrome P₄₅₀ 2D₆ Phe¹²⁰Ala mutant 作用下， 生成 4-[(2R)-2-(甲基氨基)丙基]苯-1,2-二醇 、 (R)-N-Hydroxy-Methylenedioxymethamphetamine 、 (-)-Tenamfetamine
  参考文献：
  名称：

  Metabolic Regio- and Stereoselectivity of Cytochrome P450 2D6 towards 3,4-Methylenedioxy-N-alkylamphetamines:  in Silico Predictions and Experimental Validation

  摘要：

  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.

  DOI：

  10.1021/jm050338+

文献信息

• 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.