1-(2,3,4,5-tetrahydro-1-methyl-2,4-dioxo-5-phenyl-1H-benzo[b][1,4]diazepin-3-yl)-3-phenylurea | 1422260-01-2

• 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: 1-(2,3,4,5-tetrahydro-1-methyl-2,4-dioxo-5-phenyl-1H-benzo[b][1,4]diazepin-3-yl)-3-phenylurea
• CAS: 1422260-01-2
• 化学式: C₂₃H₂₀N₄O₃
• 分子量: 400.437
• InChiKey: IWWJYTICAFGDNR-HXUWFJFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.52
• 重原子数：
  30.0
• 可旋转键数：
  3.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  81.75
• 氢给体数：
  2.0
• 氢受体数：
  3.0

反应信息

• 作为产物：
  描述：

  3-(2-phenylhydrazono)-1-methyl-5-phenyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione 在 溶剂黄146 、 锌 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 1-(2,3,4,5-tetrahydro-1-methyl-2,4-dioxo-5-phenyl-1H-benzo[b][1,4]diazepin-3-yl)-3-phenylurea 、 1-(2,3,4,5-tetrahydro-1-methyl-2,4-dioxo-5-phenyl-1H-benzo[b][1,4]diazepin-3-yl)-3-phenylurea
  参考文献：
  名称：

  Distinct CCK-2 Receptor Conformations Associated with β-Arrestin-2 Recruitment or Phospholipase-C Activation Revealed by a Biased Antagonist

  摘要：

  Seven-transmembrane receptors (7TMRs), also termed G protein-coupled receptors (GPCRs), form the largest class of cell surface membrane receptors, involving several hundred members in the human genome. Nearly 30% of marketed pharmacological agents target 7TMRs. 7TMRs adopt multiple conformations upon agonist binding. Biased agonists, in contrast to non-biased agonists, are believed to stabilize conformations preferentially activating either G-protein- or beta-arrestin-dependent signaling pathways. However, proof that cognate conformations of receptors display structural differences within their binding site where biased agonism initiates, are still lacking. Here, we show that a non-biased agonist, chole-cystokinin (CCK) induces conformational states of the CCK2R activating Gq-protein-dependent pathway (CCK2R(G)) or recruiting beta-arrestin2 (CCK2R(beta)) that are pharmacologically and structurally distinct. Two structurally unrelated antagonists competitively inhibited both pathways. A third ligand (GV150013X) acted as a high affinity competitive antagonist on CCK2R(G) but was nearly inefficient as inhibitor of CCK2R(beta). Several structural elements on both GV150013X and in CCK2R binding cavity, which hinder binding of GV150013X only to the CCK2R(beta) were identified. At last, proximity between two conserved amino acids from transmembrane helices 3 and 7 interacting through sulfur aromatic interaction was shown to be crucial for selective stabilization of the CCK2R(beta) state. These data establish structural evidence for distinct conformations of a 7TMR associated with beta-arrestin-2 recruitment or G-protein coupling and validate relevance of the design of biased ligands able to selectively target each functional conformation of 7TMRs.

  DOI：

  10.1021/ja308784w