3-bromo-N-(4-((2,3-dihydro-1H-inden-2-yl)methyl)phenyl)propanamide | 1426063-37-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 茚满类
• 英文名称: 3-bromo-N-(4-((2,3-dihydro-1H-inden-2-yl)methyl)phenyl)propanamide
• 英文别名: 3-bromo-N-[4-(2,3-dihydro-1H-inden-2-ylmethyl)phenyl]propanamide
• CAS: 1426063-37-7
• 化学式: C₁₉H₂₀BrNO
• 分子量: 358.278
• InChiKey: UOCMHOIDRQSQRM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  29.1
• 氢给体数：
  1
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  3-bromo-N-(4-((2,3-dihydro-1H-inden-2-yl)methyl)phenyl)propanamide 在 三氟甲磺酸 、 palladium 10% on activated carbon 、 盐酸羟胺 、 氢气 、 sodium acetate 、 溶剂黄146 、 sodium t-butanolate 作用下， 以 甲醇 、 乙醇 、 水 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 20.0 ℃ 、275.8 kPa 条件下， 生成 6-((2,3-dihydro-1H-inden-2-yl)methyl)-1,2,3,4-tetrahydroquinolin-4-amine
  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
• 作为产物：
  描述：

  2-(4-nitrobenzylidene)-2,3-dihydro-1H-inden-1-one 在 盐酸 、 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 作用下， 以 甲醇 、 二氯甲烷 、 水 为溶剂， 20.0 ℃ 、344.75 kPa 条件下， 生成 3-bromo-N-(4-((2,3-dihydro-1H-inden-2-yl)methyl)phenyl)propanamide
  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

• 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.
• 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.