1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one | 21988-49-8

• 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: 1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one
• 英文别名: 1-<3-(4-Phenyl-piperazino)-propyl>-3,4-dihydro-carbostyril；1-[3-(4-phenyl-piperazin-1-yl)-propyl]-3,4-dihydro-1H-quinolin-2-one；2(1h)-Quinolinone,3,4-dihydro-1-[3-(4-phenyl-1-piperazinyl)propyl]-；1-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydroquinolin-2-one
• CAS: 21988-49-8
• 化学式: C₂₂H₂₇N₃O
• 分子量: 349.476
• InChiKey: ABOBMBIQQPJTMJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  26.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one 在 dimethylsulfide borane complex 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 以59%的产率得到1-(3-(4-phenylpiperazin-1-yl)propyl)-1,2,3,4-tetrahydroquinoline
  参考文献：
  名称：

  高效和选择性多巴胺 D4 受体拮抗剂可能对治疗胶质母细胞瘤有用

  摘要：

  为了更好地了解多巴胺D 4受体（D 4 R）在胶质母细胞瘤（GBM）中的作用，本文从脑渗透剂和D 4 R选择性入手，发现了对D 4 R具有高亲和力和选择性的新配体。先导化合物1-(3-(4-苯基哌嗪-1-基)丙基)-3,4-二氢喹啉-2(1 H )-一( 6 )。特别是，D 4 R 拮抗剂24在系列中表现出比 D 2 R 和 D 3 R最高的亲和力和选择性（D 2 /D 4 = 8318，D 3 /D 4= 3715)，偏向配体29，部分激活 D 4 R G i -/G o -蛋白并阻断 β-抑制蛋白募集，成为最有趣的化合物。这些化合物经过评估其 GBM 抗肿瘤活性，诱导 GBM 细胞系和原代 GBM 干细胞 (GSC#83) 的活力降低，在 10 μM 浓度下达到最大功效。有趣的是，与替莫唑胺（GBM 中的首选化疗药物）相比，使用化合物24和29的治疗诱导了降低细胞活力的增强作用。

  DOI：

  10.1021/acs.jmedchem.2c00840
• 作为产物：
  描述：

  1-(3-bromopropyl)-3,4-dihydroquinolin-2(1H)-one 、 N-苯基哌嗪 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.25h， 以59%的产率得到1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one
  参考文献：
  名称：

  1-[3-(4-Butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1) as a Model for the Rational Design of a Novel Class of Brain Penetrant Ligands with High Affinity and Selectivity for Dopamine D₄ Receptor

  摘要：

  In the present article, the M1 mAChR bitopic agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 1) has been demonstrated to show unexpected D4R selectivity over D2R and D3R and to behave as a D4R antagonist. To better understand the structural features required for the selective interaction with the D4R and to obtain compounds unable to activate mAChRs, the aliphatic butyl chain and the piperidine nucleus of 1 were modified, affording compounds 2-14. The 4-benzylpiperidine 9 and the 4-phenylpiperazine 12 showed high D4R affinity and selectivity not only over the other D2-like subtypes, but also over M1-M5 mAChRs. Derivative 12 was also highly selective over some selected off-targets. This compound showed biased behavior, potently and partially activating Gi protein and inhibiting β-arrestin2 recruitment in functional studies. Pharmacokinetic studies demonstrated that it was characterized by a relevant brain penetration. Therefore, 12 might be a useful tool to better clarify the role played by D4R in disorders in which this subtype is involved.

  DOI：

  10.1021/acs.jmedchem.8b00265

文献信息

• 1-[3-(4-Butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1) as a Model for the Rational Design of a Novel Class of Brain Penetrant Ligands with High Affinity and Selectivity for Dopamine D₄ Receptor
  作者：Fabio Del Bello、Alessandro Bonifazi、Gianfabio Giorgioni、Carlo Cifani、Maria Vittoria Micioni Di Bonaventura、Riccardo Petrelli、Alessandro Piergentili、Stefano Fontana、Valerio Mammoli、Hideaki Yano、Rosanna Matucci、Giulio Vistoli、Wilma Quaglia

  DOI：10.1021/acs.jmedchem.8b00265

  日期：2018.4.26

  In the present article, the M1 mAChR bitopic agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 1) has been demonstrated to show unexpected D4R selectivity over D2R and D3R and to behave as a D4R antagonist. To better understand the structural features required for the selective interaction with the D4R and to obtain compounds unable to activate mAChRs, the aliphatic butyl chain and the piperidine nucleus of 1 were modified, affording compounds 2-14. The 4-benzylpiperidine 9 and the 4-phenylpiperazine 12 showed high D4R affinity and selectivity not only over the other D2-like subtypes, but also over M1-M5 mAChRs. Derivative 12 was also highly selective over some selected off-targets. This compound showed biased behavior, potently and partially activating Gi protein and inhibiting β-arrestin2 recruitment in functional studies. Pharmacokinetic studies demonstrated that it was characterized by a relevant brain penetration. Therefore, 12 might be a useful tool to better clarify the role played by D4R in disorders in which this subtype is involved.
• Highly Potent and Selective Dopamine D₄ Receptor Antagonists Potentially Useful for the Treatment of Glioblastoma
  作者：Pegi Pavletić、Ana Semeano、Hideaki Yano、Alessandro Bonifazi、Gianfabio Giorgioni、Alessandro Piergentili、Wilma Quaglia、Maria Giovanna Sabbieti、Dimitrios Agas、Giorgio Santoni、Roberto Pallini、Lucia Ricci-Vitiani、Emanuela Sabato、Giulio Vistoli、Fabio Del Bello

  DOI：10.1021/acs.jmedchem.2c00840

  日期：2022.9.22

  understand the role of dopamine D4 receptor (D4R) in glioblastoma (GBM), in the present paper, new ligands endowed with high affinity and selectivity for D4R were discovered starting from the brain penetrant and D4R selective lead compound 1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (6). In particular, the D4R antagonist 24, showing the highest affinity and selectivity over D2R and D3R

  为了更好地了解多巴胺D 4受体（D 4 R）在胶质母细胞瘤（GBM）中的作用，本文从脑渗透剂和D 4 R选择性入手，发现了对D 4 R具有高亲和力和选择性的新配体。先导化合物1-(3-(4-苯基哌嗪-1-基)丙基)-3,4-二氢喹啉-2(1 H )-一( 6 )。特别是，D 4 R 拮抗剂24在系列中表现出比 D 2 R 和 D 3 R最高的亲和力和选择性（D 2 /D 4 = 8318，D 3 /D 4= 3715)，偏向配体29，部分激活 D 4 R G i -/G o -蛋白并阻断 β-抑制蛋白募集，成为最有趣的化合物。这些化合物经过评估其 GBM 抗肿瘤活性，诱导 GBM 细胞系和原代 GBM 干细胞 (GSC#83) 的活力降低，在 10 μM 浓度下达到最大功效。有趣的是，与替莫唑胺（GBM 中的首选化疗药物）相比，使用化合物24和29的治疗诱导了降低细胞活力的增强作用。