(R)-5-(methylamino)-1-(2-(2-(2-(4-phenylbutoxy)ethoxy)ethoxy)ethyl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: (R)-5-(methylamino)-1-(2-(2-(2-(4-phenylbutoxy)ethoxy)ethoxy)ethyl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one
• 英文别名: (10R)-10-(methylamino)-3-[2-[2-[2-(4-phenylbutoxy)ethoxy]ethoxy]ethyl]-1,3-diazatricyclo[6.3.1.04,12]dodeca-4,6,8(12)-trien-2-one
• 化学式: C₂₇H₃₇N₃O₄
• 分子量: 467.608
• InChiKey: QCZAQDDIFCRXPX-XMMPIXPASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  34
• 可旋转键数：
  15
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  63.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  三乙二醇二(对甲苯磺酸酯) 在 sodium hydride 、 potassium carbonate 作用下， 以 四氢呋喃 、 丙酮 为溶剂， 反应 3.0h， 生成 (R)-5-(methylamino)-1-(2-(2-(2-(4-phenylbutoxy)ethoxy)ethoxy)ethyl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one
  参考文献：
  名称：

  Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D₂ Receptor (D₂R) Biased Agonism

  摘要：

  The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or beta-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-S-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by G(i/o)-proteins, while reducing or suppressing potency and efficacy toward beta-arrestin recruitment. Compound 19 was identified as a new lead for its selective D-2 G-protein biased agonism with an EC50 in the subnanomolar range. Structure activity correlations were observed between substitutions in positions N-1 and/or N-5 of 1 and the capacity of the new bivalent compounds to selectively activate G-proteins versus beta-arrestin recruitment in D2R-BRET functional assays.

  DOI：

  10.1021/acs.jmedchem.6b01875

文献信息

• Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D₂ Receptor (D₂R) Biased Agonism
  作者：Alessandro Bonifazi、Hideaki Yano、Michael P. Ellenberger、Ludovic Muller、Vivek Kumar、Mu-Fa Zou、Ning Sheng Cai、Adrian M. Guerrero、Amina S. Woods、Lei Shi、Amy Hauck Newman

  DOI：10.1021/acs.jmedchem.6b01875

  日期：2017.4.13

  The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or beta-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-S-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by G(i/o)-proteins, while reducing or suppressing potency and efficacy toward beta-arrestin recruitment. Compound 19 was identified as a new lead for its selective D-2 G-protein biased agonism with an EC50 in the subnanomolar range. Structure activity correlations were observed between substitutions in positions N-1 and/or N-5 of 1 and the capacity of the new bivalent compounds to selectively activate G-proteins versus beta-arrestin recruitment in D2R-BRET functional assays.