6-benzyl-2,3-dihydroquinolin-4(1H)-one | 218297-73-5

• 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-benzyl-2,3-dihydroquinolin-4(1H)-one
• 英文别名: 6-benzyl-2,3-dihydro-1H-quinolin-4-one
• CAS: 218297-73-5
• 化学式: C₁₆H₁₅NO
• 分子量: 237.301
• InChiKey: VYMDGCYNKDQWDK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 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-benzyl-2,3-dihydroquinolin-4(1H)-one 在 钯 (NH₃OH)SO₄ 、 氢气 、 1-羟基苯并三唑 、 溶剂黄146 、 N,N'-二环己基碳二亚胺 作用下， 以 乙醇 为溶剂， 生成
  参考文献：
  名称：

  Design of a high affinity peptidomimetic opioid agonist from peptide pharmacophore models

  摘要：

  A pair of diastereomeric peptidomimetics based upon opioid receptor-binding pharmacophore models derived for a series of opioid tetrapeptides was synthesized. Both analogues display high opioid receptor affinity, moderate selectivity for the mu opioid receptor, and are potent, full agonists. (C) 1998 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(98)00472-7
• 作为产物：
  描述：

  1-(4-benzylphenyl)azetidin-2-one 在 三氟甲磺酸 作用下， 生成 6-benzyl-2,3-dihydroquinolin-4(1H)-one
  参考文献：
  名称：

  新型 C-8 取代四氢喹啉作为平衡亲和力 Mu/Delta 阿片配体治疗疼痛的合成和药理学评价

  摘要：

  使用阿片类药物治疗疼痛虽然在很大程度上有效，但受到有害副作用的限制，包括镇痛耐受性、身体依赖性和欣快感，这可能导致阿片类药物滥用。研究表明，具有 μ-阿片受体 (MOR) 激动剂/δ-阿片受体 (DOR) 拮抗剂特性的化合物可减少或消除其中一些副作用，包括耐受性和依赖性的发展。在此我们报告了一系列基于四氢喹啉的拟肽的合成和药理学评价，这些肽模拟物在 C-8 位有取代。相对于我们没有 C-8 取代的主要拟肽，该系列提供了 DOR 亲和力的增加，并在 MOR 和 DOR 结合亲和力方面提供了更大的平衡。而且，在 C-8 处具有羰基部分的化合物显示出所需的 MOR 激动剂/DOR 拮抗剂特征，而烷基取代引起适度的 DOR 激动作用。该系列中的几种化合物在体内产生强大的镇痛作用，并在小鼠腹膜内给药后显示镇痛活性超过 2 小时。

  DOI：

  10.1021/acschemneuro.8b00139

文献信息

• 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。
• 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.
• 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.
• Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy μ-Opioid Receptor (MOR) Agonists/δ-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities
  作者：Aubrie A. Harland、Larisa Yeomans、Nicholas W. Griggs、Jessica P. Anand、Irina D. Pogozheva、Emily M. Jutkiewicz、John R. Traynor、Henry I. Mosberg

  DOI：10.1021/acs.jmedchem.5b01270

  日期：2015.11.25

  In a previously described peptidomimetic series, we reported the development of bifunctional ?-opioid receptor (MOR) agonist and delta-opioid receptor (DOR) antagonist ligands with a lead compound that produced antinociception for 1 h after intraperitoneal administration in mice. In this paper, we expand on our original series by presenting two modifications, both of which were designed with the following objectives: (1) probing bioavailability and improving metabolic stability, (2) balancing affinities between MOR and DOR while reducing affinity and efficacy at the kappa-opioid receptor (KOR), and (3) improving in vivo efficacy. Here, we establish that, through N-acetylation of our original peptidomimetic series, we are able to improve DOR affinity and increase selectivity relative to KOR while maintaining the desired MOR agonist/DOR antagonist profile. From initial in vivo studies, one compound (14a) was found to produce dose-dependent antinociception after peripheral administration with an improved duration of action of longer than 3 h.