6-(naphthalen-2-ylmethyl)-2,3-dihydroquinolin-4(1H)-one | 1426063-44-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 6-(naphthalen-2-ylmethyl)-2,3-dihydroquinolin-4(1H)-one
• 英文别名: 6-(naphthalen-2-ylmethyl)-2,3-dihydro-1H-quinolin-4-one
• CAS: 1426063-44-6
• 化学式: C₂₀H₁₇NO
• 分子量: 287.361
• InChiKey: VISWEMXHSBVCII-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  29.1
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  6-(naphthalen-2-ylmethyl)-2,3-dihydroquinolin-4(1H)-one 在 titanium(IV) tetraethanolate 、 sodium tetrahydroborate 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 (R)-N-((R)-1-(cyclopropanecarbonyl)-6-(naphthalen-2-ylmethyl)-1,2,3,4-tetrahydroquinolin-4-yl)-2-methylpropane-2-sulfinamide
  参考文献：
  名称：

  通过结构-活性关系（SAR）矩阵探索了双重药理学：对有效的双功能阿片样物质配体设计的见解。

  摘要：

  短效μ阿片受体（MOR）激动剂长期以来一直用于治疗严重的突破性疼痛。然而，由于依赖性，耐受性和呼吸抑制的高风险，包括芬太尼和吗啡衍生物在内的选择性MOR激动剂在临床上受到限制。我们最近报道了在小鼠中缺乏耐受性或依赖性的长效，双功能MOR激动剂/δ阿片受体（DOR）拮抗剂镇痛剂的开发（AAH8，此后称为2B）。为了满足对突破性疼痛的短效治疗的需求，我们提出了一系列在体内具有抗伤害感受活性的新型，短效，高效MOR激动剂/ DOR拮抗剂配体。在这项研究中，我们利用二维结构-活性关系矩阵来确定可归因于化学型内两个关键药效基团元素组合的药理趋势。这项工作增强了我们调节MOR和DOR功效的能力，可访问多种双功能谱，同时在两个受体上均保持高亲和力和效力。

  DOI：

  10.1021/acs.jmedchem.9b00378
• 作为产物：
  描述：

  2-(4-nitrobenzyl)naphthalene 在 盐酸 、 三氟甲磺酸 、 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 、 sodium t-butanolate 作用下， 以 甲醇 、 二氯甲烷 、 水 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 20.0 ℃ 、344.75 kPa 条件下， 生成 6-(naphthalen-2-ylmethyl)-2,3-dihydroquinolin-4(1H)-one
  参考文献：
  名称：

  Opioid Peptidomimetics: Leads for the Design of Bioavailable Mixed Efficacy μ Opioid Receptor (MOR) Agonist/δ Opioid Receptor (DOR) Antagonist Ligands

  摘要：

  We have previously described opioid peptidomimetic, 1, employing a tetrahydroquinoline scaffold and modeled on a series of cyclic tetrapeptide opioid agonists. We have recently described modifications to these peptides that confer a mu opioid receptor (MOR) agonist, delta opioid receptor (DOR) antagonist profile, which has been shown to reduce the development of tolerance to the analgesic actions of MOR agonists. Several such bifunctional ligands have been reported, but none has been demonstrated to cross the blood-brain barrier. Here we describe the transfer of structural features that evoked MOR agonist/DOR antagonist behavior in the cyclic peptides to the tetrahydroquinoline scaffold and show that the resulting peptidomimetics maintain the desired pharmacological profile. Further, the 4R diastereomer of 1 was fully efficacious and approximately equipotent to morphine in the mouse warm water tail withdrawal assay following intraperitoneal administration and thus a promising lead for the development of opioid analgesics with reduced tolerance.

  DOI：

  10.1021/jm400050y

文献信息

• Peptidomimetics and Methods of Using the Same
  申请人：The Regents of the University of Michigan

  公开号：US20180072677A1

  公开（公告）日：2018-03-15

  Disclosed herein are compounds useful for modulating the mu-opioid receptor (“MOR”) and/or delta-opioid receptor (“DOR”), and methods of using these compounds to treat diseases and conditions, such as pain. In particular, disclosed herein are compounds of Formula (I) and pharmaceutically acceptable salt thereof: wherein the substituents are as described.

  本文披露了一些有用于调节μ-阿片受体（“MOR”）和/或δ-阿片受体（“DOR”）的化合物，以及使用这些化合物治疗疾病和病况（如疼痛）的方法。具体来说，本文披露了一些符合下列式（I）的化合物及其药用可接受的盐：其中取代基如所述。
• Effects of <i>N</i>-Substitutions on the Tetrahydroquinoline (THQ) Core of Mixed-Efficacy μ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Ligands
  作者：Aubrie A. Harland、Aaron M. Bender、Nicholas W. Griggs、Chao Gao、Jessica P. Anand、Irina D. Pogozheva、John R. Traynor、Emily M. Jutkiewicz、Henry I. Mosberg

  DOI：10.1021/acs.jmedchem.6b00308

  日期：2016.5.26

  N-Acetylation of the tetrahydroquinoline (THQ) core of a series of mu-opioid receptor (MOR) agonist/delta-opioid receptor (DOR) antagonist ligands increases DOR affinity, resulting in ligands with balanced MOR and DOR affinities. We report a series of N-substituted THQ analogues that incorporate various carbonyl-containing moieties to maintain DOR affinity and define the steric and electronic requirements of the binding pocket across the opioid receptors. 4h produced in vivo antinociception (ip) for 1 h at 10 mg/kg.
• [EN] PEPTIDOMIMETICS AND METHODS OF USING THE SAME<br/>[FR] PEPTIDOMIMÉTIQUES ET SES PROCÉDÉS D'UTILISATION
  申请人：UNIV MICHIGAN REGENTS

  公开号：WO2018053240A1

  公开（公告）日：2018-03-22

  Disclosed herein are compounds useful for modulating the mu-opioid receptor ("MOR") and/or delta-opioid receptor ("DOR"), and methods of using these compounds to treat diseases and conditions, such as pain. In particular, disclosed herein are compounds of Formula (I) and pharmaceutically acceptable salt thereof: (I), wherein the substituents are as described.
• Dual Pharmacophores Explored via Structure–Activity Relationship (SAR) Matrix: Insights into Potent, Bifunctional Opioid Ligand Design
  作者：Anthony F. Nastase、Jessica P. Anand、Aaron M. Bender、Deanna Montgomery、Nicholas W. Griggs、Thomas J. Fernandez、Emily M. Jutkiewicz、John R. Traynor、Henry I. Mosberg

  DOI：10.1021/acs.jmedchem.9b00378

  日期：2019.4.25

  Short-acting μ-opioid receptor (MOR) agonists have long been used for the treatment of severe, breakthrough pain. However, selective MOR agonists including fentanyl and morphine derivatives are limited clinically due to high risks of dependence, tolerance, and respiratory depression. We recently reported the development of a long-acting, bifunctional MOR agonist/δ-opioid receptor (DOR) antagonist analgesic

  短效μ阿片受体（MOR）激动剂长期以来一直用于治疗严重的突破性疼痛。然而，由于依赖性，耐受性和呼吸抑制的高风险，包括芬太尼和吗啡衍生物在内的选择性MOR激动剂在临床上受到限制。我们最近报道了在小鼠中缺乏耐受性或依赖性的长效，双功能MOR激动剂/δ阿片受体（DOR）拮抗剂镇痛剂的开发（AAH8，此后称为2B）。为了满足对突破性疼痛的短效治疗的需求，我们提出了一系列在体内具有抗伤害感受活性的新型，短效，高效MOR激动剂/ DOR拮抗剂配体。在这项研究中，我们利用二维结构-活性关系矩阵来确定可归因于化学型内两个关键药效基团元素组合的药理趋势。这项工作增强了我们调节MOR和DOR功效的能力，可访问多种双功能谱，同时在两个受体上均保持高亲和力和效力。
• Opioid Peptidomimetics: Leads for the Design of Bioavailable Mixed Efficacy μ Opioid Receptor (MOR) Agonist/δ Opioid Receptor (DOR) Antagonist Ligands
  作者：Henry I. Mosberg、Larisa Yeomans、Aubrie A. Harland、Aaron M. Bender、Katarzyna Sobczyk-Kojiro、Jessica P. Anand、Mary J. Clark、Emily M. Jutkiewicz、John R. Traynor

  DOI：10.1021/jm400050y

  日期：2013.3.14

  We have previously described opioid peptidomimetic, 1, employing a tetrahydroquinoline scaffold and modeled on a series of cyclic tetrapeptide opioid agonists. We have recently described modifications to these peptides that confer a mu opioid receptor (MOR) agonist, delta opioid receptor (DOR) antagonist profile, which has been shown to reduce the development of tolerance to the analgesic actions of MOR agonists. Several such bifunctional ligands have been reported, but none has been demonstrated to cross the blood-brain barrier. Here we describe the transfer of structural features that evoked MOR agonist/DOR antagonist behavior in the cyclic peptides to the tetrahydroquinoline scaffold and show that the resulting peptidomimetics maintain the desired pharmacological profile. Further, the 4R diastereomer of 1 was fully efficacious and approximately equipotent to morphine in the mouse warm water tail withdrawal assay following intraperitoneal administration and thus a promising lead for the development of opioid analgesics with reduced tolerance.