(3S)-1-[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]-N-[(2S)-1-[[(1S)-2-carbamoyl-1-phenylprop-2-enyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pyrrolidine-3-carboxamide | 1427063-04-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: (3S)-1-[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]-N-[(2S)-1-[[(1S)-2-carbamoyl-1-phenylprop-2-enyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pyrrolidine-3-carboxamide
• CAS: 1427063-04-4
• 化学式: C₃₅H₃₈N₆O₅
• 分子量: 622.724
• InChiKey: AGAQXKAFDAOXKW-GLWIQRGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  46
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  184
• 氢给体数：
  6
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  tert-butyl N-[(1S)-2-dimethoxyphosphoryl-3-oxo-1-phenyl-3-pyrrol-1-ylpropyl]carbamate 在 盐酸 、 水 、 sodium methylate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 25.5h， 生成 (3S)-1-[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]-N-[(2S)-1-[[(1S)-2-carbamoyl-1-phenylprop-2-enyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pyrrolidine-3-carboxamide
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Characterization of Novel Endomorphin-1 Analogues as Extremely Potent μ-Opioid Agonists

  摘要：

  Recently we reported the synthesis and structure activity study of endomorphin-1 (EM-1) analogues containing novel, unnatural alpha-methylene-beta-aminopropanoic acids (Map). In the present study, we describe new EM-1 analogues containing Dmt(1), (R/S)-beta Pro(2), and (ph)Map(4)/(2-furyl)Map(4). All of the analogues showed a high affinity for the mu-opioid receptor (MOR) and increased stability in mouse brain homogenates. Of the new compounds, Dmt(1)-(R)-beta Pro(2)-Trp(3)-(2-furyl)Map(4) (analogue 12) displayed the highest affinity toward MOR, in the picomolar range (K-i(mu) = 3.72 pM). Forskolin-induced cAMP accumulation assays indicated that this analogue displayed an extremely high agonistic potency, in the subpicomolar range (EC50 = 0.0421 pM, E-max = 99.5%). This compound also displayed stronger in vivo antinociceptive activity after iv administration when compared to morphine in the tail-flick test, which indicates that this analogue was able to cross the blood-brain barrier.

  DOI：

  10.1021/jm400195y

文献信息

• Design, Synthesis, and Pharmacological Characterization of Novel Endomorphin-1 Analogues as Extremely Potent μ-Opioid Agonists
  作者：Xin Liu、Yuan Wang、Yanhong Xing、Jing Yu、Hong Ji、Ming Kai、Zilong Wang、Dan Wang、Yixin Zhang、Depeng Zhao、Rui Wang

  DOI：10.1021/jm400195y

  日期：2013.4.11

  Recently we reported the synthesis and structure activity study of endomorphin-1 (EM-1) analogues containing novel, unnatural alpha-methylene-beta-aminopropanoic acids (Map). In the present study, we describe new EM-1 analogues containing Dmt(1), (R/S)-beta Pro(2), and (ph)Map(4)/(2-furyl)Map(4). All of the analogues showed a high affinity for the mu-opioid receptor (MOR) and increased stability in mouse brain homogenates. Of the new compounds, Dmt(1)-(R)-beta Pro(2)-Trp(3)-(2-furyl)Map(4) (analogue 12) displayed the highest affinity toward MOR, in the picomolar range (K-i(mu) = 3.72 pM). Forskolin-induced cAMP accumulation assays indicated that this analogue displayed an extremely high agonistic potency, in the subpicomolar range (EC50 = 0.0421 pM, E-max = 99.5%). This compound also displayed stronger in vivo antinociceptive activity after iv administration when compared to morphine in the tail-flick test, which indicates that this analogue was able to cross the blood-brain barrier.