17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(5'-fluoro-2'-indolyl)acetamido]morphinan

• 分子结构分类: 有机化合物 - 苯类化合物 - 菲及其衍生物
• 英文名称: 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(5'-fluoro-2'-indolyl)acetamido]morphinan
• 英文别名: N-[(4R,4aS,7R,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl]-5-fluoro-1H-indole-2-carboxamide
• 化学式: C₂₉H₃₀FN₃O₄
• 分子量: 503.573
• InChiKey: ADBBOEMTJLDNGP-XSGLBDKUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  37
• 可旋转键数：
  4
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  97.8
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  5-氟吲哚-2-甲酸 、 (5alpha,6beta)-6-氨基-17-(环丙基甲基)-4,5-环氧-吗喃-3,14-二醇 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 以89%的产率得到17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(5'-fluoro-2'-indolyl)acetamido]morphinan
  参考文献：
  名称：

  Putative Kappa Opioid Heteromers As Targets for Developing Analgesics Free of Adverse Effects

  摘要：

  It is now generally recognized that upon activation by an agonist, β-arrestin associates with G protein-coupled receptors and acts as a scaffold in creating a diverse signaling network that could lead to adverse effects. As an approach to reducing side effects associated with κ opioid agonists, a series of β-naltrexamides 3-10 was synthesized in an effort to selectively target putative κ opioid heteromers without recruiting β-arrestin upon activation. The most potent derivative 3 (INTA) strongly activated KOR-DOR and KOR-MOR heteromers in HEK293 cells. In vivo studies revealed 3 to produce potent antinociception, which, when taken together with antagonism data, was consistent with the activation of both heteromers. 3 was devoid of tolerance, dependence, and showed no aversive effect in the conditioned place preference assay. As immunofluorescence studies indicated no recruitment of β-arrestin2 to membranes in coexpressed KOR-DOR cells, this study suggests that targeting of specific putative heteromers has the potential to identify leads for analgesics devoid of adverse effects.

  DOI：

  10.1021/jm500159d

文献信息

• Putative Kappa Opioid Heteromers As Targets for Developing Analgesics Free of Adverse Effects
  作者：Morgan Le Naour、Mary M. Lunzer、Michael D. Powers、Alexander E. Kalyuzhny、Michael A. Benneyworth、Mark J. Thomas、Philip S. Portoghese

  DOI：10.1021/jm500159d

  日期：2014.8.14

  It is now generally recognized that upon activation by an agonist, β-arrestin associates with G protein-coupled receptors and acts as a scaffold in creating a diverse signaling network that could lead to adverse effects. As an approach to reducing side effects associated with κ opioid agonists, a series of β-naltrexamides 3-10 was synthesized in an effort to selectively target putative κ opioid heteromers without recruiting β-arrestin upon activation. The most potent derivative 3 (INTA) strongly activated KOR-DOR and KOR-MOR heteromers in HEK293 cells. In vivo studies revealed 3 to produce potent antinociception, which, when taken together with antagonism data, was consistent with the activation of both heteromers. 3 was devoid of tolerance, dependence, and showed no aversive effect in the conditioned place preference assay. As immunofluorescence studies indicated no recruitment of β-arrestin2 to membranes in coexpressed KOR-DOR cells, this study suggests that targeting of specific putative heteromers has the potential to identify leads for analgesics devoid of adverse effects.