2-[[4-(2,3-dihydro-1,4-benzodioxan-5-yl)piperazin-1-yl]methyl]-1,3-dioxoperhydroimidazo[1,5-a]pyridine

• 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: 2-[[4-(2,3-dihydro-1,4-benzodioxan-5-yl)piperazin-1-yl]methyl]-1,3-dioxoperhydroimidazo[1,5-a]pyridine
• 英文别名: 2-[[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]methyl]-6,7,8,8a-tetrahydro-5H-imidazo[1,5-a]pyridine-1,3-dione
• 化学式: C₂₀H₂₆N₄O₄
• 分子量: 386.451
• InChiKey: ZSXABQYFCRYXPU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  65.6
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  聚合甲醛 、 1-(2,3-二氢-1,4-苯并二烷-5-基)哌嗪盐酸盐 、 四氢咪唑并[1,5-a]吡啶-1,3(2H,5H)-二酮 以 甲醇 、 水 为溶剂， 以88%的产率得到2-[[4-(2,3-dihydro-1,4-benzodioxan-5-yl)piperazin-1-yl]methyl]-1,3-dioxoperhydroimidazo[1,5-a]pyridine
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 8. Computational Simulation of Ligand−Receptor Interaction of 5-HT_1AR Agonists with Selectivity over α₁-Adrenoceptors

  摘要：

  We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT1AR affinity and selectivity over alpha(1)-adrenoceptors. The new selective 5-HT1AR ligands contain a hydantoin (m = 0) or diketopiperazine (m = 1) moiety and an arylpiperazine moiety separated by one methylene unit (n = 1). The aryl substituent of the piperazine moiety (Ar) consists of different benzofused rings mimicking the favorable voluminous substituents at ortho and meta positions predicted by 3D-QSAR analysis in the previously reported series I. In particular, (S)-2-[[4-(naphth-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine [(S)-9, CSP-2503] (5-HT1A, K-i = 4.1 nM; alpha(1), Ki > 1000 nM) has been pharmacologically characterized as a 5-HT1AR agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties. Ligand (S)-9 is predicted, in computer simulations, to bind Asp(3.32) in TMH 3, Thr(5.39) and Ser(5.42) in TMH 5, and Trp(6.48) in TMH 6. We propose that agonists modify, by means of an explicit hydrogen bond, the conformation of Trp(6.48) from pointing toward TMH 7, in the inactive gauche+ conformation, to pointing toward the ligand binding site, in the active trans conformation.

  DOI：

  10.1021/jm048999e

文献信息

• Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 8. Computational Simulation of Ligand−Receptor Interaction of 5-HT_1AR Agonists with Selectivity over α₁-Adrenoceptors
  作者：María L. López-Rodríguez、Maria José Morcillo、Esther Fernández、Bellinda Benhamú、Ignacio Tejada、David Ayala、Alma Viso、Mercedes Campillo、Leonardo Pardo、Mercedes Delgado、Jorge Manzanares、José A. Fuentes

  DOI：10.1021/jm048999e

  日期：2005.4.1

  We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT1AR affinity and selectivity over alpha(1)-adrenoceptors. The new selective 5-HT1AR ligands contain a hydantoin (m = 0) or diketopiperazine (m = 1) moiety and an arylpiperazine moiety separated by one methylene unit (n = 1). The aryl substituent of the piperazine moiety (Ar) consists of different benzofused rings mimicking the favorable voluminous substituents at ortho and meta positions predicted by 3D-QSAR analysis in the previously reported series I. In particular, (S)-2-[[4-(naphth-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine [(S)-9, CSP-2503] (5-HT1A, K-i = 4.1 nM; alpha(1), Ki > 1000 nM) has been pharmacologically characterized as a 5-HT1AR agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties. Ligand (S)-9 is predicted, in computer simulations, to bind Asp(3.32) in TMH 3, Thr(5.39) and Ser(5.42) in TMH 5, and Trp(6.48) in TMH 6. We propose that agonists modify, by means of an explicit hydrogen bond, the conformation of Trp(6.48) from pointing toward TMH 7, in the inactive gauche+ conformation, to pointing toward the ligand binding site, in the active trans conformation.