2,3-dihydroxy-11-methoxytetrahydroprotoberberine | 1470017-29-8

• 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-dihydroxy-11-methoxytetrahydroprotoberberine
• 英文别名: 11-methoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline-2,3-diol
• CAS: 1470017-29-8
• 化学式: C₁₈H₁₉NO₃
• 分子量: 297.354
• InChiKey: QENRDSSNVLVQMF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  52.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2,3-dihydroxy-11-methoxytetrahydroprotoberberine 、 N,N-二甲基甲酰胺 在 cesium fluoride 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以86%的产率得到2,3-methylendioxy-11-methoxytetrahydroprotoberberine
  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：

  2,3-dibenzyloxy-11-methoxytetrahydroprotoberberine 在 盐酸 作用下， 以 乙醇 为溶剂， 反应 3.0h， 以33%的产率得到2,3-dihydroxy-11-methoxytetrahydroprotoberberine
  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

• [EN] HEXAHYDRODIBENZO[A,G]QUINOLIZINE COMPOUND, PREPARATION METHOD THEREFOR, PHARMACEUTICAL COMPOSITION AND USE THEREOF<br/>[FR] COMPOSÉ D'HEXAHYDRODIBENZO[A,G]QUINOLIZINE, SON PROCÉDÉ DE PRÉPARATION, COMPOSITION PHARMACEUTIQUE ET SON UTILISATION
  申请人：SHANGHAI INST MATERIA MEDICA

  公开号：WO2012163179A1

  公开（公告）日：2012-12-06

  发明涉及一种具有通式(I)所示的新颖的六氢二苯并[a,g]喹嗪类化合物及其衍生物，其对映异构体、非对映异构体、外消旋体及其混合物，及其药学上可接受的盐。本发明还涉及该类化合物的制备方法，另外该类化合物对神经系统疾病，特别是与多巴胺受体和五羟色胺受体相关的疾病有较好的防治作用。生物学活性实验表明，该类化合物有望开发成为一类治疗与多巴胺受体及五羟色胺受体相关的疾病特别是精神分裂症、帕金森氏症、药物成瘾性、偏头痛等疾病的强效的新化学实体。
• 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.