3-(trans-4-(2-(5-chloro-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1,1-dimethylurea

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: 3-(trans-4-(2-(5-chloro-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1,1-dimethylurea
• 化学式: C₂₀H₃₀ClN₃O
• 分子量: 363.931
• InChiKey: AFAMVWBXPZJINL-JCNLHEQBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.92
• 重原子数：
  25.0
• 可旋转键数：
  4.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  35.58
• 氢给体数：
  1.0
• 氢受体数：
  2.0

反应信息

• 作为产物：
  描述：

  N-[trans-4-[[(methylsulfonyl)oxy]methyl]cyclohexyl]carbamic acid tert-butyl ester 在 三乙酰氧基硼氢化钠 、 二异丁基氢化铝 、 三乙胺 、 三氟乙酸 作用下， 以 正己烷 、 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 7.0h， 生成 3-(trans-4-(2-(5-chloro-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1,1-dimethylurea
  参考文献：
  名称：

  D₂ Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine

  摘要：

  Functionally selective G protein-coupled receptor ligands are valuable tools for deciphering the roles of downstream signaling pathways that potentially contribute to therapeutic effects versus side effects. Recently, we discovered both G(i/o)-biased and beta-arrestin2-biased D-2 receptor agonists based on the Food and Drug Administration (FDA)-approved drug aripiprazole. In this work, based on another FDA-approved drug, cariprazine, we conducted a structure-functional selectivity relationship study and discovered compound 38 (MS1768) as a potent partial agonist that selectively activates the G(i/o) pathway over beta-arrestin2. Unlike the dual D2R/D3R partial agonist cariprazine, compound 38 showed selective agonist activity for D2R over D3R. In fact, compound 38 exhibited potent antagonism of dopamine-stimulated beta-arrestin2 recruitment. In our docking studies, compound 38 directly interacts with S193(5.42) on TM5 but has no interactions with extracellular loop 2, which appears to be in contrast to the binding poses of D2R beta-arrestin2-biased ligands. In in vivo studies, compound 38 showed high D2R receptor occupancy in mice and effectively inhibited phencyclidine-induced hyperlocomotion.

  DOI：

  10.1021/acs.jmedchem.9b00508

文献信息

• D₂ Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine
  作者：Yudao Shen、John D. McCorvy、Michael L. Martini、Ramona M. Rodriguiz、Vladimir M. Pogorelov、Karen M. Ward、William C. Wetsel、Jing Liu、Bryan L. Roth、Jian Jin

  DOI：10.1021/acs.jmedchem.9b00508

  日期：2019.5.9

  Functionally selective G protein-coupled receptor ligands are valuable tools for deciphering the roles of downstream signaling pathways that potentially contribute to therapeutic effects versus side effects. Recently, we discovered both G(i/o)-biased and beta-arrestin2-biased D-2 receptor agonists based on the Food and Drug Administration (FDA)-approved drug aripiprazole. In this work, based on another FDA-approved drug, cariprazine, we conducted a structure-functional selectivity relationship study and discovered compound 38 (MS1768) as a potent partial agonist that selectively activates the G(i/o) pathway over beta-arrestin2. Unlike the dual D2R/D3R partial agonist cariprazine, compound 38 showed selective agonist activity for D2R over D3R. In fact, compound 38 exhibited potent antagonism of dopamine-stimulated beta-arrestin2 recruitment. In our docking studies, compound 38 directly interacts with S193(5.42) on TM5 but has no interactions with extracellular loop 2, which appears to be in contrast to the binding poses of D2R beta-arrestin2-biased ligands. In in vivo studies, compound 38 showed high D2R receptor occupancy in mice and effectively inhibited phencyclidine-induced hyperlocomotion.