5,6,13,13a-tetrahydro-2,3,11-trimethoxy-8H-dibenzoquinolizine | 19778-14-4

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 原小檗碱生物碱及其衍生物
• 英文名称: 5,6,13,13a-tetrahydro-2,3,11-trimethoxy-8H-dibenzoquinolizine
• 英文别名: 2,3,11-trimethoxytetrahydroprotoberberine；(S)-2,3,11-trimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g] quinolizine；2,3,11-Trimethoxytetrahydroberberin；2,3,13-Trimethoxy-berbin；2,3,11-trimethoxy-5,8,13,13a-tetrahydro-6H-isoquino[3,2-a]isoquinoline；(+/-)-2,3,11-Trimethoxy-berbin；2,3,11-trimethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline
• CAS: 19778-14-4
• 化学式: C₂₀H₂₃NO₃
• 分子量: 325.408
• InChiKey: HQWHBNSOZIKJSG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  30.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5,6,13,13a-tetrahydro-2,3,11-trimethoxy-8H-dibenzoquinolizine 在 三溴化硼 、 cesium fluoride 作用下， 以 二氯甲烷 为溶剂， 反应 5.25h， 生成 2,3-methylenedioxy-11-hydroxytetrahydroprotoberberine
  参考文献：
  名称：

  2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands

  摘要：

  Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new dopamine receptors (DR) acting drugs as potential new targets for the treatment of schizophrenia or Parkinson's disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) and tetrahydroprotoberberines (THPBs) can behave as selective D-2 dopaminergic alkaloids since they share structural similarities with dopamine. In the present study we have synthesized eleven 2,3,9- and 2,3,11-trisubstituted THPB compounds (six of them are described for the first time) and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D-1 and D-2 DR and establish the structure activity relationship (SAR) as dopaminergic agents. In general, all the tested THPBs with protected phenolic hydroxyls showed a lower affinity for D-1 and D-2 DR than their corresponding homologues with free hydroxyl groups. In previous studies in which dopaminergic affinity of 1-benzyl-THIQs (BTHIQs) was evaluated, the presence of a Cl into the A-ring resulted in increased affinity and selectivity towards D-2 DR. This is in contrast with the current study since the existence of a chlorine atom into the A-ring of the THPBs caused increased affinity for D-1 DR but dramatically reduced the selectivity for D-2 DR. An OH group in position 9 of the THPB (9f) resulted in a higher affinity for DR than its homologue with an OH group in position 11 (9e) (250 fold for D-2 DR). None of the compounds showed any cytotoxicity in freshly isolated human neutrophils. A molecular modelling study of three representative THPBs was carried out. The combination of MD simulations with DFT calculations provided a clear picture of the ligand binding interactions from a structural and energetic point of view. Therefore, it is likely that compound 9d (2,3,9-trihydroxy-THPB) behave as D-2 DR agonist since serine residues cluster are crucial for agonist binding and receptor activation. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.07.036
• 作为产物：
  描述：

  6,7-二甲氧基-3,4-二氢异喹啉 在 carbon monoxide,cobalt,cyclopenta-1,3-diene 氢氧化钾 、 三氟乙酸 作用下， 以 四氯化碳 、 乙醇 、 间二甲苯 为溶剂， 反应 14.5h， 生成 5,6,13,13a-tetrahydro-2,3,11-trimethoxy-8H-dibenzoquinolizine
  参考文献：
  名称：

  区域选择性钴催化的原小ber碱合成中的辅助硅

  摘要：

  η 5 -环戊二烯基二羰基钴催化的1,2-双（炔丙基）-1,2,3,4-四氢异喹啉的cocyclization 4B和5与炔烃是提供一种新颖的合成进入tetrahydroprotoberberine细胞核。通过明智地选择三甲基甲硅烷基取代基，可以实现D环中的区域控制。的反应4B与在催化剂的存在下苄腈配料的稀土异奎诺[2,1- b ] -2,6-萘啶骨架，也区域选择性。

  DOI：

  10.1016/s0040-4020(01)88589-6

文献信息

• 2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands
  作者：Javier Párraga、Nuria Cabedo、Sebastián Andujar、Laura Piqueras、Laura Moreno、Abraham Galán、Emilio Angelina、Ricardo D. Enriz、María Dolores Ivorra、María Jesús Sanz、Diego Cortes

  DOI：10.1016/j.ejmech.2013.07.036

  日期：2013.10

  Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new dopamine receptors (DR) acting drugs as potential new targets for the treatment of schizophrenia or Parkinson's disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) and tetrahydroprotoberberines (THPBs) can behave as selective D-2 dopaminergic alkaloids since they share structural similarities with dopamine. In the present study we have synthesized eleven 2,3,9- and 2,3,11-trisubstituted THPB compounds (six of them are described for the first time) and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D-1 and D-2 DR and establish the structure activity relationship (SAR) as dopaminergic agents. In general, all the tested THPBs with protected phenolic hydroxyls showed a lower affinity for D-1 and D-2 DR than their corresponding homologues with free hydroxyl groups. In previous studies in which dopaminergic affinity of 1-benzyl-THIQs (BTHIQs) was evaluated, the presence of a Cl into the A-ring resulted in increased affinity and selectivity towards D-2 DR. This is in contrast with the current study since the existence of a chlorine atom into the A-ring of the THPBs caused increased affinity for D-1 DR but dramatically reduced the selectivity for D-2 DR. An OH group in position 9 of the THPB (9f) resulted in a higher affinity for DR than its homologue with an OH group in position 11 (9e) (250 fold for D-2 DR). None of the compounds showed any cytotoxicity in freshly isolated human neutrophils. A molecular modelling study of three representative THPBs was carried out. The combination of MD simulations with DFT calculations provided a clear picture of the ligand binding interactions from a structural and energetic point of view. Therefore, it is likely that compound 9d (2,3,9-trihydroxy-THPB) behave as D-2 DR agonist since serine residues cluster are crucial for agonist binding and receptor activation. (C) 2013 Elsevier Masson SAS. All rights reserved.
• Auxiliary silicon in regioselective cobalt catalyzed protoberberine syntheses
  作者：Russell L. Hillard、Carol A. Parnell、K.Peter C. Vollhardt

  DOI：10.1016/s0040-4020(01)88589-6

  日期：1983.1

  η5-Cyclopentadienyl dicarbonyl cobalt catalyzes the cocyclization of 1,2-bis(propargyl)-1,2,3,4-tetrahydroisoquinolines 4b and 5 with alkynes to provide a novel synthetic entry into the tetrahydroprotoberberine nucleus. By judicious choice of trimethylsilyl substituents, regiocontrol in the D-ring can be achieved. Reaction of 4b with benzonitrile in the presence of the catalyst furnishes the rare isoquino[2

  η 5 -环戊二烯基二羰基钴催化的1,2-双（炔丙基）-1,2,3,4-四氢异喹啉的cocyclization 4B和5与炔烃是提供一种新颖的合成进入tetrahydroprotoberberine细胞核。通过明智地选择三甲基甲硅烷基取代基，可以实现D环中的区域控制。的反应4B与在催化剂的存在下苄腈配料的稀土异奎诺[2,1- b ] -2,6-萘啶骨架，也区域选择性。