ethyl (trans-4-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate

• 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: ethyl (trans-4-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate
• 英文别名: ethyl (4-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate
• 化学式: C₂₀H₃₀N₂O₂
• 分子量: 330.47
• InChiKey: YAQRLZQYOQZQDV-RUCARUNLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.74
• 重原子数：
  24.0
• 可旋转键数：
  5.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  41.57
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为产物：
  描述：

  (trans-4-Aminocyclohexyl)acetic acid 在 盐酸 、 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 二氯甲烷 、 水 、 1,2-二氯乙烷 、 甲苯 为溶剂， 反应 16.0h， 生成 ethyl (trans-4-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate
  参考文献：
  名称：

  A Structure–Activity Analysis of Biased Agonism at the Dopamine D2 Receptor

  摘要：

  Biased agonism offers an opportunity for the medicinal chemist to discover pathway-selective ligands for GPCRs. A number of studies have suggested that biased agonism at the dopamine D2 receptor (D2R) may be advantageous for the treatment of neuropsychiatric disorders, including schizophrenia. As such, it is of great importance to gain insight into the SAR of biased agonism at this receptor. We have generated SAR based on a novel D2R partial agonist, tert-butyl (trans-4-(2-(3,4dihydroisoquinolin-2(1H)-yOethyl)cyclohexyl)carbamate (4). This ligand shares structural similarity to cariprazine (2), a drug awaiting FDA approval for the treatment of schizophrenia, yet displays a distinct bias toward two different signaling end points. We synthesized a number of derivatives of 4 with subtle structural modifications, including incorporation of cariprazine fragments. By combining pharmacological profiling with analytical methodology to identify and to quantify bias, we have demonstrated that efficacy and biased agonism can be finely tuned by minor structural modifications to the head group containing the tertiary amine, a tail group that extends away from this moiety, and the orientation and length of a spacer region between these two moieties.

  DOI：

  10.1021/jm401318w

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.
• A Structure–Activity Analysis of Biased Agonism at the Dopamine D2 Receptor
  作者：Jeremy Shonberg、Carmen Klein Herenbrink、Laura López、Arthur Christopoulos、Peter J. Scammells、Ben Capuano、J. Robert Lane

  DOI：10.1021/jm401318w

  日期：2013.11.27

  Biased agonism offers an opportunity for the medicinal chemist to discover pathway-selective ligands for GPCRs. A number of studies have suggested that biased agonism at the dopamine D2 receptor (D2R) may be advantageous for the treatment of neuropsychiatric disorders, including schizophrenia. As such, it is of great importance to gain insight into the SAR of biased agonism at this receptor. We have generated SAR based on a novel D2R partial agonist, tert-butyl (trans-4-(2-(3,4dihydroisoquinolin-2(1H)-yOethyl)cyclohexyl)carbamate (4). This ligand shares structural similarity to cariprazine (2), a drug awaiting FDA approval for the treatment of schizophrenia, yet displays a distinct bias toward two different signaling end points. We synthesized a number of derivatives of 4 with subtle structural modifications, including incorporation of cariprazine fragments. By combining pharmacological profiling with analytical methodology to identify and to quantify bias, we have demonstrated that efficacy and biased agonism can be finely tuned by minor structural modifications to the head group containing the tertiary amine, a tail group that extends away from this moiety, and the orientation and length of a spacer region between these two moieties.