7-methylsulfonyl-N-triphenylmethyl-1,2,3,4-tetrahydroisoquinoline | 220247-64-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: 7-methylsulfonyl-N-triphenylmethyl-1,2,3,4-tetrahydroisoquinoline
• 英文别名: 7-methylsulfonyl-2-trityl-3,4-dihydro-1H-isoquinoline
• CAS: 220247-64-3
• 化学式: C₂₉H₂₇NO₂S
• 分子量: 453.605
• InChiKey: FXTJNIMIJLXCBK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  45.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  四氯化碳 、 7-methylsulfonyl-N-triphenylmethyl-1,2,3,4-tetrahydroisoquinoline 在 正丁基锂 作用下， 生成 7-sulfonyl-THIQ 11
  参考文献：
  名称：

  Synthesis, Biochemical Evaluation, and Classical and Three-Dimensional Quantitative Structure−Activity Relationship Studies of 7-Substituted-1,2,3,4-tetrahydroisoquinolines and Their Relative Affinities toward Phenylethanolamine N-Methyltransferase and the α₂-Adrenoceptor^,1

  摘要：

  7-Substituted-1,2,3,4-tetrahydroisoquinolines (7-substituted-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), the enzyme involved in the biosynthesis of epinephrine. Unfortunately, most of these compounds also exhibit strong affinity for the aa-adrenoceptor. To design a selective (PNMT vs alpha(2)-adrenoceptor affinity) inhibitor of PNMT, the steric and electrostatic factors responsible for PNMT inhibitory activity and alpha(2)-adrenoceptor affinity were investigated by evaluating a number of 7-substituted-THIQs. A classical quantitative structure-activity relationship (QSAR) study resulted in a three-parameter equation for PNMT (PNMT pK(i) = 0.599 pi - 0.0725MR + 1.55 sigma(m) + 5.80; n = 27, r = 0.885, s = 0.573) and a three-parameter equation for the alpha(2)-adrenoceptor (alpha(2) pK(i) = 0.599 pi - 0.0542MR - 0.951 sigma(m) + 6.45; n = 27, r = 0.917, s = 0.397). These equations indicated that steric effects and lipophilicity play a similar role at either active site but that electronic effects play opposite roles at either active site. Two binding orientations for the THIQs were postulated such that lipophilic and hydrophilic 7-substituents would not occupy the same region of space at either binding site. Using these two binding orientations, based on the lipophilicity of the 7-substituent, comparative molecular field analysis (CoMFA) models were developed that showed that the steric and electrostatic interactions at both sites were similar to those previously elaborated in the QSAR analyses. Both the QSAR and the CoMFA analyses showed that the steric interactions are similar at the PNMT active site and at the alpha(2)-adrenoceptor and that the electrostatic interactions were different at the two sites. This difference in electrostatic interactions might be responsible for the selectivity of THIQs bearing a nonlipophilic electron-withdrawing group at the 7-position, These QSAR and CoMFA results will be useful in the design of potent and selective (PNMT vs alpha(2)-adrenoceptor affinity) inhibitors of PNMT.

  DOI：

  10.1021/jm980429p
• 作为产物：
  描述：

  7-Methylsulfanyl-1,2,3,4-tetrahydro-isoquinoline 在 4-二甲氨基吡啶 、 三氟过氧乙酸 、 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 42.0h， 生成 7-methylsulfonyl-N-triphenylmethyl-1,2,3,4-tetrahydroisoquinoline
  参考文献：
  名称：

  Synthesis, Biochemical Evaluation, and Classical and Three-Dimensional Quantitative Structure−Activity Relationship Studies of 7-Substituted-1,2,3,4-tetrahydroisoquinolines and Their Relative Affinities toward Phenylethanolamine N-Methyltransferase and the α₂-Adrenoceptor^,1

  摘要：

  7-Substituted-1,2,3,4-tetrahydroisoquinolines (7-substituted-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), the enzyme involved in the biosynthesis of epinephrine. Unfortunately, most of these compounds also exhibit strong affinity for the aa-adrenoceptor. To design a selective (PNMT vs alpha(2)-adrenoceptor affinity) inhibitor of PNMT, the steric and electrostatic factors responsible for PNMT inhibitory activity and alpha(2)-adrenoceptor affinity were investigated by evaluating a number of 7-substituted-THIQs. A classical quantitative structure-activity relationship (QSAR) study resulted in a three-parameter equation for PNMT (PNMT pK(i) = 0.599 pi - 0.0725MR + 1.55 sigma(m) + 5.80; n = 27, r = 0.885, s = 0.573) and a three-parameter equation for the alpha(2)-adrenoceptor (alpha(2) pK(i) = 0.599 pi - 0.0542MR - 0.951 sigma(m) + 6.45; n = 27, r = 0.917, s = 0.397). These equations indicated that steric effects and lipophilicity play a similar role at either active site but that electronic effects play opposite roles at either active site. Two binding orientations for the THIQs were postulated such that lipophilic and hydrophilic 7-substituents would not occupy the same region of space at either binding site. Using these two binding orientations, based on the lipophilicity of the 7-substituent, comparative molecular field analysis (CoMFA) models were developed that showed that the steric and electrostatic interactions at both sites were similar to those previously elaborated in the QSAR analyses. Both the QSAR and the CoMFA analyses showed that the steric interactions are similar at the PNMT active site and at the alpha(2)-adrenoceptor and that the electrostatic interactions were different at the two sites. This difference in electrostatic interactions might be responsible for the selectivity of THIQs bearing a nonlipophilic electron-withdrawing group at the 7-position, These QSAR and CoMFA results will be useful in the design of potent and selective (PNMT vs alpha(2)-adrenoceptor affinity) inhibitors of PNMT.

  DOI：

  10.1021/jm980429p