threo-4-hydroxy-N-methyl-methylphenidate

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: threo-4-hydroxy-N-methyl-methylphenidate
• 英文别名: (R)-(4-Hydroxy-phenyl)-((R)-1-methyl-piperidin-2-yl)-acetic acid methyl ester；methyl (2R)-2-(4-hydroxyphenyl)-2-[(2R)-1-methylpiperidin-2-yl]acetate
• 化学式: C₁₅H₂₁NO₃
• 分子量: 263.337
• InChiKey: GFHAGFCWXOFKEL-ZIAGYGMSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  聚合甲醛 、 哌醋右甲酯 在 甲酸 作用下， 反应 2.0h， 以28 mg的产率得到
  参考文献：
  名称：

  Quantitative structure–activity relationship studies of threo-methylphenidate analogs

  摘要：

  Complementary two-dimensional (2D) and three-dimensional (3D) Quantitative Structure-Activity Relationship (QSAR) techniques were used to derive a preliminary model for the dopamine transporter (DAT) binding affinity of 80 racemic threo-methylphenidate (MP) analogs. A novel approach based on using the atom-level E-state indices of the 14 common scaffold atoms in a sphere exclusion protocol was used to identify a test set for 2D-and 3D-QSAR model validation. Comparative Molecular Field Analysis (CoMFA) contour maps based on the structure-activity data of the training set indicate that the 2' position of the phenyl ring cannot tolerate much steric bulk and that addition of electron-withdrawing groups to the 3' or 40 positions of the phenyl ring leads to improved DAT binding affinity. In particular, the optimal substituents were found to be those whose bulk is mainly in the plane of the phenyl ring. Substituents with significant bulk above or below the plane of the ring led to decreased binding affinity. Suggested alterations to be explored in the design of new compounds are the placement at the 3' and 4' position of the phenyl ring of electron-withdrawing groups that lie chiefly in the plane of the ring, for example, halogen substituents on the 3',4'-benzo analog, 79. A complementary 2D-QSAR approach-partial least squares analysis using a reduced set of Molconn-Z descriptors-supports the CoMFA structure-activity interpretation that phenyl ring substitution is a major determinant of DAT binding affinity. The potential usefulness of the CoMFA models was demonstrated by the prediction of the binding affinity of methyl 2-(naphthalen-1-yl)-2-(piperidin-2-yl) acetate, an analog not in the original data set, to be in good agreement with the experimental value. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.08.034

文献信息

• Quantitative structure–activity relationship studies of threo-methylphenidate analogs
  作者：Milind Misra、Qing Shi、Xiaocong Ye、Ewa Gruszecka-Kowalik、Wei Bu、Zhanzhu Liu、Margaret M. Schweri、Howard M. Deutsch、Carol A. Venanzi

  DOI：10.1016/j.bmc.2010.08.034

  日期：2010.10.15

  Complementary two-dimensional (2D) and three-dimensional (3D) Quantitative Structure-Activity Relationship (QSAR) techniques were used to derive a preliminary model for the dopamine transporter (DAT) binding affinity of 80 racemic threo-methylphenidate (MP) analogs. A novel approach based on using the atom-level E-state indices of the 14 common scaffold atoms in a sphere exclusion protocol was used to identify a test set for 2D-and 3D-QSAR model validation. Comparative Molecular Field Analysis (CoMFA) contour maps based on the structure-activity data of the training set indicate that the 2' position of the phenyl ring cannot tolerate much steric bulk and that addition of electron-withdrawing groups to the 3' or 40 positions of the phenyl ring leads to improved DAT binding affinity. In particular, the optimal substituents were found to be those whose bulk is mainly in the plane of the phenyl ring. Substituents with significant bulk above or below the plane of the ring led to decreased binding affinity. Suggested alterations to be explored in the design of new compounds are the placement at the 3' and 4' position of the phenyl ring of electron-withdrawing groups that lie chiefly in the plane of the ring, for example, halogen substituents on the 3',4'-benzo analog, 79. A complementary 2D-QSAR approach-partial least squares analysis using a reduced set of Molconn-Z descriptors-supports the CoMFA structure-activity interpretation that phenyl ring substitution is a major determinant of DAT binding affinity. The potential usefulness of the CoMFA models was demonstrated by the prediction of the binding affinity of methyl 2-(naphthalen-1-yl)-2-(piperidin-2-yl) acetate, an analog not in the original data set, to be in good agreement with the experimental value. (C) 2010 Elsevier Ltd. All rights reserved.