6β-N-(glycylglycyl)naltrexamine | 103304-83-2

• 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: 6β-N-(glycylglycyl)naltrexamine
• CAS: 103304-83-2
• 化学式: C₂₄H₃₂N₄O₅
• 分子量: 456.542
• InChiKey: PSOGCPNSPIROTB-WRQPYSRYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.48
• 重原子数：
  33.0
• 可旋转键数：
  6.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  137.15
• 氢给体数：
  5.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  6β-N-(glycylglycyl)naltrexamine 在 4-二甲氨基吡啶 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 [9-[4-[[2-[[2-[[(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]amino]-2-oxoethyl]amino]-2-oxoethyl]carbamothioylamino]-2-carboxyphenyl]-6-(diethylamino)xanthen-3-ylidene]-diethylazanium
  参考文献：
  名称：

  Synthesis and evaluation of a ligand targeting the μ and δ opioid receptors for drug delivery to lung cancer

  摘要：

  A well-established approach to developing new imaging agents and treatments for cancer begins with the recognition of receptors that are overexpressed in cancer cells. Ideally, these same receptors would also be absent, or minimally expressed, in healthy tissue. The mu (mu) and delta (delta) opioid receptors (MOR and DOR respectively) match these criteria, with expression in cancer cells that is higher than primary lung epithelial cells. Naltrexone is a drug approved by the U.S. Food and Drug Administration (FDA) for treatment of alcohol dependence or prevention of relapse from opioid addiction. Since naltrexone binds with high affinity to both MOR and DOR, it was selected as the platform for development of novel ligands capable of delivering a cytotoxic payload to non-small cell lung cancer (NSCLC). This study outlines the synthesis of two ligands, with peptide or PEG linkers that were synthesized from 6-amino-naltrexone and conjugated with rhodamine dye or Tc-99m for in vitro imaging, binding affinity or in vivo imaging and biodistribution studies. Transfected HEK cells were used as a model system for over-expression of the mu-opioid receptor (MOR) or the delta-opioid receptor (DOR). Naltrexone and naltrindole were used as competition for MOR and DOR respectively during the binding affinity studies. Mice bearing a xenograft of HEI( cells transfected with mu (HEK-mu) or delta (HEK-delta) opioid receptors were the animal model used for PET imaging and in vivo biodistribution studies. Although the binding affinity studies were encouraging, the biodistribution data for the selected conjugates lacked sufficient specificity. These conjugates were abandoned from further development but information about their synthesis may be valuable to other laboratories working in this field. (C) 2016 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2016.06.067
• 作为产物：
  描述：

  纳曲酮 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 、 N,N-双(2-苯基乙基)胺盐酸盐 作用下， 生成 6β-N-(glycylglycyl)naltrexamine
  参考文献：
  名称：

  Synthesis and evaluation of a ligand targeting the μ and δ opioid receptors for drug delivery to lung cancer

  摘要：

  A well-established approach to developing new imaging agents and treatments for cancer begins with the recognition of receptors that are overexpressed in cancer cells. Ideally, these same receptors would also be absent, or minimally expressed, in healthy tissue. The mu (mu) and delta (delta) opioid receptors (MOR and DOR respectively) match these criteria, with expression in cancer cells that is higher than primary lung epithelial cells. Naltrexone is a drug approved by the U.S. Food and Drug Administration (FDA) for treatment of alcohol dependence or prevention of relapse from opioid addiction. Since naltrexone binds with high affinity to both MOR and DOR, it was selected as the platform for development of novel ligands capable of delivering a cytotoxic payload to non-small cell lung cancer (NSCLC). This study outlines the synthesis of two ligands, with peptide or PEG linkers that were synthesized from 6-amino-naltrexone and conjugated with rhodamine dye or Tc-99m for in vitro imaging, binding affinity or in vivo imaging and biodistribution studies. Transfected HEK cells were used as a model system for over-expression of the mu-opioid receptor (MOR) or the delta-opioid receptor (DOR). Naltrexone and naltrindole were used as competition for MOR and DOR respectively during the binding affinity studies. Mice bearing a xenograft of HEI( cells transfected with mu (HEK-mu) or delta (HEK-delta) opioid receptors were the animal model used for PET imaging and in vivo biodistribution studies. Although the binding affinity studies were encouraging, the biodistribution data for the selected conjugates lacked sufficient specificity. These conjugates were abandoned from further development but information about their synthesis may be valuable to other laboratories working in this field. (C) 2016 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2016.06.067

文献信息

• Synthesis and opioid antagonist potencies of naltrexamine bivalent ligands with conformationally restricted spacers
  作者：P. S. Portoghese、G. Ronsisvalle、D. L. Larson、A. E. Takemori

  DOI：10.1021/jm00159a014

  日期：1986.9

  was found that the fumaryl and succinyl series (11) possessed a very similar structure-potency profile with respect to antagonism at mu opioid receptors, the interaction of these two series at kappa receptors differed substantially from one another. This difference was manifested by the longer spacer requirement for peak kappa antagonist potency in the fumaryl relative to the succinyl series. It is concluded

  合成了具有纳曲沙明药效基团的二价配体1-4和不同长度的含有富马酰基部分的间隔基，并评估了它们对电刺激的豚鼠回肠纵向肌肉（GPI）的μ和κ阿片样物质拮抗剂的活性。将富马芳基部分掺入间隔物中，以便确定间隔物的构象限制对间隔物长度和阿片样物质拮抗剂效力之间关系的影响。尽管发现富马芳基和琥珀酰系列（11）在μ阿片受体上的拮抗作用具有非常相似的结构效价曲线，但这两个系列在κ受体上的相互作用却存在很大差异。相对于琥珀酰系列，在富马酸中峰值κ拮抗剂效价的间隔物要求更长，表明了这种差异。结论是，在短间隔基团（n = 0）中由富马芳基施加的构象限制阻止了两个药效团与κ受体系统的邻近识别位点的有效相互作用。随着间隔物加长（n = 2）并变得更加灵活，相邻的识别位点会同时被占用，从而具有更大的便利性。