(R)-4-amino-1-(4-(2,3-dichlorophenyl)piperazin-1-yl)butan-2-ol amine | 1204186-94-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (R)-4-amino-1-(4-(2,3-dichlorophenyl)piperazin-1-yl)butan-2-ol amine
• 英文别名: (R)-4-amino-1-(4-(2,3-dichlorophenyl)piperazin-1-yl)butan-2-ol
• CAS: 1204186-94-6
• 化学式: C₁₄H₂₁Cl₂N₃O
• 分子量: 318.246
• InChiKey: ZGOOMUKHQJASFX-LLVKDONJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.83
• 重原子数：
  20.0
• 可旋转键数：
  5.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  52.73
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  吲哚-2-羧酸 、 (R)-4-amino-1-(4-(2,3-dichlorophenyl)piperazin-1-yl)butan-2-ol amine 在 1,1′-carbonyldiimidazole 作用下， 反应 3.0h， 生成 R-PG648
  参考文献：
  名称：

  Chiral Resolution and Serendipitous Fluorination Reaction for the Selective Dopamine D3 Receptor Antagonist BAK2-66

  摘要：

  The improved chiral synthesis of the selective dopamine D3 receptor (D3R) antagonist (R)-N-(4-(4-(2,3-dichlorophenyl)piperazin- I -yl) -3-hydroxybutyl)1H-indole-2carboxamide ((R)-PG648) is described. The same chiral secondary alcohol intermediate was used to prepare the enantiomers of a 3-F-benzofuranyl analogue, BAK 2-66. The absolute configurations of the 3-F enantiomers were assigned from their X-ray crystal structures that confirmed retention of configuration during fluorination with N,N-diethylaminosulfur trifluoride (DAST). (R)-BAK2-66 showed higher D3R affinity and selectivity than its (S)-enantiomer; however, it had lower D3R affinity and enantioselectivity than (R)-PG648. Further, importance of the 4-atom linker length between the aryl amide and 4-phenylpiperazine was demonstrated with the 4-fluorobutylproduct (8).

  DOI：

  10.1021/ml500006v
• 作为产物：
  描述：

  (R)-2-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)isoindoline-1,3-dione 在 肼 作用下， 以 乙醇 为溶剂， 反应 3.0h， 生成 (R)-4-amino-1-(4-(2,3-dichlorophenyl)piperazin-1-yl)butan-2-ol amine
  参考文献：
  名称：

  Chiral Resolution and Serendipitous Fluorination Reaction for the Selective Dopamine D3 Receptor Antagonist BAK2-66

  摘要：

  The improved chiral synthesis of the selective dopamine D3 receptor (D3R) antagonist (R)-N-(4-(4-(2,3-dichlorophenyl)piperazin- I -yl) -3-hydroxybutyl)1H-indole-2carboxamide ((R)-PG648) is described. The same chiral secondary alcohol intermediate was used to prepare the enantiomers of a 3-F-benzofuranyl analogue, BAK 2-66. The absolute configurations of the 3-F enantiomers were assigned from their X-ray crystal structures that confirmed retention of configuration during fluorination with N,N-diethylaminosulfur trifluoride (DAST). (R)-BAK2-66 showed higher D3R affinity and selectivity than its (S)-enantiomer; however, it had lower D3R affinity and enantioselectivity than (R)-PG648. Further, importance of the 4-atom linker length between the aryl amide and 4-phenylpiperazine was demonstrated with the 4-fluorobutylproduct (8).

  DOI：

  10.1021/ml500006v

文献信息

• Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D₃ Receptor
  作者：Mayako Michino、Comfort A. Boateng、Prashant Donthamsetti、Hideaki Yano、Oluyomi M. Bakare、Alessandro Bonifazi、Michael P. Ellenberger、Thomas M. Keck、Vivek Kumar、Clare Zhu、Ravi Verma、Jeffrey R. Deschamps、Jonathan A. Javitch、Amy Hauck Newman、Lei Shi

  DOI：10.1021/acs.jmedchem.6b01148

  日期：2017.1.26

  Both dopamine D3 receptor (D3R) partial agonists and antagonists have been implicated as potential medications for substance use disorders. In contrast to antagonists, partial agonists may cause fewer side effects since they maintain some dopaminergic tone and may be less disruptive to normal neuronal functions. Here, we report three sets of 4-phenylpiperazine stereoisomers that differ considerably

  多巴胺D 3受体（D 3 R）部分激动剂和拮抗剂均被认为是药物滥用障碍的潜在药物。与拮抗剂相比，部分激动剂可保持较少的多巴胺能基调，因此对副作用的影响较小，并且对正常神经元功能的破坏较小。在这里，我们报告三套4-苯基哌嗪立体异构体，它们的功效差异很大：（R）-对映异构体是拮抗剂/弱部分激动剂，而（S）-对映异构体则更为有效。为了研究部分激动剂的结构基础，我们从D 3的非活性状态开始进行了比较微秒级的分子动力学模拟R与这些对映异构体复合。对模拟结果的分析揭示了由结合的（S）-对映异构体而不是（R）-对映异构体诱导的配体结合位点附近的常见结构重排，其为部分活化的受体构象的特征。这些与部分激动剂结合的受体模型可用于具有定制功效特征的化合物的基于结构的设计。