6-Bromo-7-methoxy-1-phenyl-3,4-dihydro-isoquinoline | 159465-29-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氢异喹啉
• 英文名称: 6-Bromo-7-methoxy-1-phenyl-3,4-dihydro-isoquinoline
• 英文别名: 6-Bromo-7-methoxy-1-phenyl-3,4-dihydroisoquinoline
• CAS: 159465-29-9
• 化学式: C₁₆H₁₄BrNO
• 分子量: 316.197
• InChiKey: CLNLIUAJYYHFHE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  21.6
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  6-Bromo-7-methoxy-1-phenyl-3,4-dihydro-isoquinoline 在 sodium tetrahydroborate 、 溶剂黄146 作用下， 以 甲醇 为溶剂， 以57%的产率得到6-Bromo-7-methoxy-1-phenyl-1,2,3,4-tetrahydro-isoquinoline
  参考文献：
  名称：

  Synthesis and Molecular Modeling of 1-Phenyl-1,2,3,4-tetrahydroisoquinolines and Related 5,6,8,9-Tetrahydro-13bH-dibenzo[a,h]quinolizines as D1 Dopamine Antagonists

  摘要：

  New 1-phenyl-1,2,3,4-tetrahydroisoquinolines and related 5,6,8,9-tetrahydro-13bH-dibenzo[a,h]-quinolizines were prepared as ring-contracted analogs of the prototypical 1-phenyl-2,3,4,5-tetrahydrobenzazepines (e.g., SCH23390) as a continuation of our studies to characterize the antagonist binding pharmacophore of the D-1 dopamine receptor. Receptor affinity was assessed by competition for [H-3]SCH23390 binding sites in rat striatal membranes. The 6-bromo-1-phenyltetrahydroisoquinoline analog 2 of SCH23390 1 had D-1 binding affinity similar to that for the previously reported 6-chloro analog 6, whereas the 6,7-dihydroxy analog 5 had significantly lower D-1 affinity. Conversely, neither 6-monohydroxy- (3) nor 7-monohydroxy-1-phenyltetrahydroisoquinolines (4) had significant affinity for the D-1 receptor. These results demonstrate that 6-halo and 7-hydroxy substituents influence D-1 binding affinity of the 1-phenyltetrahydroisoquinolines in a fashion similar to their effects on 1-phenyltetrahydrobenzazepines. azepines. The conformationally constrained 3-chloro-2-hydroxytetrahydrodibenzoquinolizine 9 had much lower affinity relative to the corresponding, and more flexible, 6-chloro-7-hydroxy-1-phenyltetrahydroisoquinoline 6. Similarly, 2,3-dihydroxytetrahydrodibenzoquinolizine 10 had much lower D-1 affinity compared to dihydrexidine 14, a structurally similar hexahydrobenzo[a]phenanthridine that is a high-affinity full D-1 agonist. Together, these data not only confirm the effects of the halo and hydroxy substitutents on the parent nucleus but demonstrate the pharmacophoric importance of both the nitrogen position and the orientation of the accessory phenyl ring in modulating D-1 receptor affinity and function. Molecular modeling studies and conformational analyses were conducted using the data from these new analogs in combination with the data from compounds previously synthesized. The resulting geometries were used to refine a working model of the D-1 antagonist pharmacophore using conventional quantitative structure-activity relationships and three-dimensional QSAR (CoMFA).

  DOI：

  10.1021/jm00051a008
• 作为产物：
  描述：

  2-(3-溴-4-甲氧基苯基)乙胺 在 sodium hydroxide 、 phosphorus pentoxide 、 三氯氧磷 作用下， 以 乙醚 、 xylene 为溶剂， 反应 6.0h， 生成 6-Bromo-7-methoxy-1-phenyl-3,4-dihydro-isoquinoline
  参考文献：
  名称：

  Synthesis and Molecular Modeling of 1-Phenyl-1,2,3,4-tetrahydroisoquinolines and Related 5,6,8,9-Tetrahydro-13bH-dibenzo[a,h]quinolizines as D1 Dopamine Antagonists

  摘要：

  New 1-phenyl-1,2,3,4-tetrahydroisoquinolines and related 5,6,8,9-tetrahydro-13bH-dibenzo[a,h]-quinolizines were prepared as ring-contracted analogs of the prototypical 1-phenyl-2,3,4,5-tetrahydrobenzazepines (e.g., SCH23390) as a continuation of our studies to characterize the antagonist binding pharmacophore of the D-1 dopamine receptor. Receptor affinity was assessed by competition for [H-3]SCH23390 binding sites in rat striatal membranes. The 6-bromo-1-phenyltetrahydroisoquinoline analog 2 of SCH23390 1 had D-1 binding affinity similar to that for the previously reported 6-chloro analog 6, whereas the 6,7-dihydroxy analog 5 had significantly lower D-1 affinity. Conversely, neither 6-monohydroxy- (3) nor 7-monohydroxy-1-phenyltetrahydroisoquinolines (4) had significant affinity for the D-1 receptor. These results demonstrate that 6-halo and 7-hydroxy substituents influence D-1 binding affinity of the 1-phenyltetrahydroisoquinolines in a fashion similar to their effects on 1-phenyltetrahydrobenzazepines. azepines. The conformationally constrained 3-chloro-2-hydroxytetrahydrodibenzoquinolizine 9 had much lower affinity relative to the corresponding, and more flexible, 6-chloro-7-hydroxy-1-phenyltetrahydroisoquinoline 6. Similarly, 2,3-dihydroxytetrahydrodibenzoquinolizine 10 had much lower D-1 affinity compared to dihydrexidine 14, a structurally similar hexahydrobenzo[a]phenanthridine that is a high-affinity full D-1 agonist. Together, these data not only confirm the effects of the halo and hydroxy substitutents on the parent nucleus but demonstrate the pharmacophoric importance of both the nitrogen position and the orientation of the accessory phenyl ring in modulating D-1 receptor affinity and function. Molecular modeling studies and conformational analyses were conducted using the data from these new analogs in combination with the data from compounds previously synthesized. The resulting geometries were used to refine a working model of the D-1 antagonist pharmacophore using conventional quantitative structure-activity relationships and three-dimensional QSAR (CoMFA).

  DOI：

  10.1021/jm00051a008

文献信息

• Synthesis and Molecular Modeling of 1-Phenyl-1,2,3,4-tetrahydroisoquinolines and Related 5,6,8,9-Tetrahydro-13bH-dibenzo[a,h]quinolizines as D1 Dopamine Antagonists
  作者：Deborah L. Minor、Steven D. Wyrick、Paul S. Charifson、Val J. Watts、David E. Nichols、Richard B. Mailman

  DOI：10.1021/jm00051a008

  日期：1994.12

  New 1-phenyl-1,2,3,4-tetrahydroisoquinolines and related 5,6,8,9-tetrahydro-13bH-dibenzo[a,h]-quinolizines were prepared as ring-contracted analogs of the prototypical 1-phenyl-2,3,4,5-tetrahydrobenzazepines (e.g., SCH23390) as a continuation of our studies to characterize the antagonist binding pharmacophore of the D-1 dopamine receptor. Receptor affinity was assessed by competition for [H-3]SCH23390 binding sites in rat striatal membranes. The 6-bromo-1-phenyltetrahydroisoquinoline analog 2 of SCH23390 1 had D-1 binding affinity similar to that for the previously reported 6-chloro analog 6, whereas the 6,7-dihydroxy analog 5 had significantly lower D-1 affinity. Conversely, neither 6-monohydroxy- (3) nor 7-monohydroxy-1-phenyltetrahydroisoquinolines (4) had significant affinity for the D-1 receptor. These results demonstrate that 6-halo and 7-hydroxy substituents influence D-1 binding affinity of the 1-phenyltetrahydroisoquinolines in a fashion similar to their effects on 1-phenyltetrahydrobenzazepines. azepines. The conformationally constrained 3-chloro-2-hydroxytetrahydrodibenzoquinolizine 9 had much lower affinity relative to the corresponding, and more flexible, 6-chloro-7-hydroxy-1-phenyltetrahydroisoquinoline 6. Similarly, 2,3-dihydroxytetrahydrodibenzoquinolizine 10 had much lower D-1 affinity compared to dihydrexidine 14, a structurally similar hexahydrobenzo[a]phenanthridine that is a high-affinity full D-1 agonist. Together, these data not only confirm the effects of the halo and hydroxy substitutents on the parent nucleus but demonstrate the pharmacophoric importance of both the nitrogen position and the orientation of the accessory phenyl ring in modulating D-1 receptor affinity and function. Molecular modeling studies and conformational analyses were conducted using the data from these new analogs in combination with the data from compounds previously synthesized. The resulting geometries were used to refine a working model of the D-1 antagonist pharmacophore using conventional quantitative structure-activity relationships and three-dimensional QSAR (CoMFA).