N1,N8-bis(3-(4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)piperazin-1-yl)propyl)octanediamide | 1357146-65-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: N1,N8-bis(3-(4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)piperazin-1-yl)propyl)octanediamide
• 英文别名: N,N'-bis[3-[4-(3-chloro-11H-benzo[b][1,4]benzodiazepin-6-yl)piperazin-1-yl]propyl]octanediamide
• CAS: 1357146-65-6
• 化学式: C₄₈H₅₈Cl₂N₁₀O₂
• 分子量: 877.96
• InChiKey: DATNAXXQOLNOOK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  62
• 可旋转键数：
  17
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  120
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  8-氯-11-(1-哌嗪基)-5H-二苯并[B,E] [1,4]吡喃 在 吡啶 、 N,N-二异丙基乙胺 、 三氟乙酸 、 sodium iodide 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 5.0h， 生成 N1,N8-bis(3-(4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)piperazin-1-yl)propyl)octanediamide
  参考文献：
  名称：

  Homobivalent Ligands of the Atypical Antipsychotic Clozapine: Design, Synthesis, and Pharmacological Evaluation

  摘要：

  To date all typical and atypical antipsychotics target the dopamine D-2 receptor. Clozapine represents the best-characterized atypical antipsychotic, although it displays only moderate (submicromolar) affinity for the dopamine D-2 receptor. Herein, we present the design, synthesis, and pharmacological evaluation of three series of homobivalent ligands of clozapine, differing in the length and nature of the spacer and the point of attachment to the pharmacophore. Attachment of the spacer at the N4' position of clozapine yielded a series of homobivalent ligands that displayed spacer-length-dependent gains in affinity and activity for the dopamine D-2 receptor. The 16 and 18 atom spacer bivalent ligands were the highlight compounds, displaying marked low nanomolar receptor binding affinity (1.41 and 1.35 nM, respectively) and functional activity (23 and 44 nM), which correspond to significant gains in affinity (75- and 79-fold) and activity (9- and 5-fold) relative to the original pharmacophore, clozapine. As such these ligands represent useful tools with which to investigate dopamine receptor dimerization and the atypical nature of clozapine.

  DOI：

  10.1021/jm201420s

文献信息

• Homobivalent Ligands of the Atypical Antipsychotic Clozapine: Design, Synthesis, and Pharmacological Evaluation
  作者：Fiona M. McRobb、Ian T. Crosby、Elizabeth Yuriev、J. Robert Lane、Ben Capuano

  DOI：10.1021/jm201420s

  日期：2012.2.23

  To date all typical and atypical antipsychotics target the dopamine D-2 receptor. Clozapine represents the best-characterized atypical antipsychotic, although it displays only moderate (submicromolar) affinity for the dopamine D-2 receptor. Herein, we present the design, synthesis, and pharmacological evaluation of three series of homobivalent ligands of clozapine, differing in the length and nature of the spacer and the point of attachment to the pharmacophore. Attachment of the spacer at the N4' position of clozapine yielded a series of homobivalent ligands that displayed spacer-length-dependent gains in affinity and activity for the dopamine D-2 receptor. The 16 and 18 atom spacer bivalent ligands were the highlight compounds, displaying marked low nanomolar receptor binding affinity (1.41 and 1.35 nM, respectively) and functional activity (23 and 44 nM), which correspond to significant gains in affinity (75- and 79-fold) and activity (9- and 5-fold) relative to the original pharmacophore, clozapine. As such these ligands represent useful tools with which to investigate dopamine receptor dimerization and the atypical nature of clozapine.