2,3,9-trimethoxy-5,6,7,8,13,13a-hexahydroisoquinolino[3,2-a]isoquinoline | 1095271-36-5

• 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: 2,3,9-trimethoxy-5,6,7,8,13,13a-hexahydroisoquinolino[3,2-a]isoquinoline
• 英文别名: 2,3,9-trimethoxytetrahydroprotoberberine；2,3,9-trimethoxy-5,6,7,8,13,13a-hexahydroisoquino[2,1-b]isoquinoline；2,3,9-trimethoxy-5,6,7,8,13,13a-hexahydroisoquino[3,2-a]isoquinoline；2,3,9-trimethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline
• CAS: 1095271-36-5
• 化学式: C₂₀H₂₃NO₃
• 分子量: 325.408
• InChiKey: BIWCHVGMGDYNNS-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：

  2,3,9-trimethoxy-5,6,7,8,13,13a-hexahydroisoquinolino[3,2-a]isoquinoline 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 2.25h， 以97%的产率得到2,3,9-trihydroxytetrahydroprotoberberine
  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：

  聚合甲醛 、 6,7-dimethoxy-1-(3'-methoxybenzyl)-1,2,3,4-THIQ hydrochloride 在 盐酸 作用下， 以 甲醇 、 乙醇 、 水 为溶剂， 反应 5.0h， 以77%的产率得到5,6,13,13a-tetrahydro-2,3,11-trimethoxy-8H-dibenzoquinolizine
  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

文献信息

• Compounds and Compositions for Modulating Lipid Levels and Methods of Preparing Same
  申请人：Liu Haiyan

  公开号：US20110009628A1

  公开（公告）日：2011-01-13

  The present technology relates to compounds of Formulas I-VI and methods of making and using such compounds. Methods of use include prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome. Compounds disclosed herein also increase HDL-C, lower total cholesterol, LDL-cholesterol, and triglycerides and increase hepatic LDL receptor expression, inhibit PCSK9 expression, and activate AMP-activated protein kinase.

  目前的技术涉及到公式I-VI的化合物以及制备和使用这些化合物的方法。使用方法包括预防和治疗高脂血症、高胆固醇血症、高甘油三酯血症、肝脂肪变性和代谢综合征。本文披露的化合物还可以增加高密度脂蛋白胆固醇（HDL-C），降低总胆固醇、低密度脂蛋白胆固醇（LDL-C）和甘油三酯，并增加肝LDL受体表达，抑制PCSK9表达，并激活AMP激活蛋白激酶。
• COMPOUNDS, COMPOSITIONS AND METHODS FOR REDUCING LIPID LEVELS
  申请人：Liu Haiyan

  公开号：US20090048246A1

  公开（公告）日：2009-02-19

  Compositions comprising extracts or isolated or purified compounds from plants of the genus Corydalis provide prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome. Corydalis compounds and their derivatives of natural and synthetic origins lower total cholesterol, LDL-cholesterol, and triglycerides and increase hepatic LDL receptor expression and activate AMP-activated protein kinase. Specific stereoisomers of Corydalis compounds with lipid lowering activity include 14R-(+)-corypalmine, 14R,13S-(+)-corydaline, 14R-(+)-tetrahydropalmatin, (+)-corlumidin, d-(+)-bicuculline, and (+)-egenine.

  从黄堇属植物提取物或分离纯化的化合物构成的组合物可预防和治疗高脂血症、高胆固醇血症、高甘油三酯血症、肝脂肪变性和代谢综合征。黄堇化合物及其天然和合成来源的衍生物可降低总胆固醇、LDL-胆固醇和甘油三酯，增加肝LDL受体表达并激活AMP激活蛋白激酶。具有降脂活性的黄堇化合物的特定立体异构体包括14R-(+)-可丹碱、14R,13S-(+)-可丹啉、14R-(+)-四氢棕榈碱、(+)-可鲁米丁、d-(+)-比库枯碱和(+)-艾根碱。
• ISOQUINOLINYL-CONTAINING ALKALOID COMPOUNDS AND COMPOSITIONS USEFUL FOR REDUCING LIPID LEVELS
  申请人：CVI Pharmaceuticals Limited

  公开号：EP2370434B1

  公开（公告）日：2014-09-17
• COMPOUNDS AND COMPOSITIONS FOR REDUCING LIPID LEVELS
  申请人：Liu Haiyan

  公开号：US20110269754A1

  公开（公告）日：2011-11-03

  Compositions comprising extracts or isolated or purified compounds from plants of the genus Corydalis provide prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome. Corydalis compounds and their derivatives of natural and synthetic origins lower total cholesterol, LDL-cholesterol, and triglycerides and increase hepatic LDL receptor expression and activate AMP-activated protein kinase. Specific stereoisomers of Corydalis compounds with lipid lowering activity include 14R-(+)-corypalmine, 14R,13S-(+)-corydaline, 14R-(+)-tetrahydropalmatin, (+)-corlumidin, d-(+)-bicuculline, and (+)-egenine.
• COMPOUNDS, COMPOSITIONS AND METHODS FOR TREATING NASH, NAFLD, AND OBESITY
  申请人：LIU Jingwen

  公开号：US20220387403A1

  公开（公告）日：2022-12-08

  The present technology relates to methods of treating NASH, NAFLD and/or obesity using compounds of Formulas I, II, III, IV, V, and/or VI. The methods include administering to a subject suffering from one or more of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) and/or obesity a therapeutically effective amount of such a compound