17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(benzothiophene-5-carboxamido)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-6α-(benzothiophene-5-carboxamido)morphinan
• 英文别名: N-[(4R,4aS,7S,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]-1-benzothiophene-5-carboxamide
• 化学式: C₂₉H₃₀N₂O₄S
• 分子量: 502.634
• InChiKey: LHLAXEAGBQYMEN-PABBMQRISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  36
• 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：
  110
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(benzothiophene-5-carboxamido)morphinan 在 盐酸 作用下， 以 甲醇 为溶剂， 生成 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(benzothiophene-5-carboxamido)morphinan hydrochloride
  参考文献：
  名称：

  Application of Bivalent Bioisostere Concept on Design and Discovery of Potent Opioid Receptor Modulators

  摘要：

  Here, we described the structural modification of previously identified it opioid receptor (MOR) antagonist NAN, a 6 alpha-N-7'-indolyl substituted naltrexamine derivative, and its 6 beta-N-2'-indolyl substituted analogue INTA by adopting the concept of "bivalent bioisostere". Three newly prepared opioid ligands, 25 (NBF), 31, and 38, were identified as potent MOR antagonists both in vitro and in vivo. Moreover, these three compounds significantly antagonized DAMGO-induced intracellular calcium flux and displayed varying degrees of inhibition on cAMP production. Furthermore, NBF produced much less significant withdrawal effects than naloxone in morphine-pelleted mice. Molecular modeling studies revealed that these bivalent bioisosteres may adopt similar binding modes in the MOR and the "address" portions of them may have negative or positive allosteric modulation effects on the function of their "message" portions compared with NAN and INTA. Collectively, our successful application of the "bivalent bioisostere concept" identified a promising lead to develop novel therapeutic agents toward opioid use disorder treatments.

  DOI：

  10.1021/acs.jmedchem.9b01767
• 作为产物：
  描述：

  纳曲酮 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 苄胺 作用下， 以 N,N-二甲基甲酰胺 、 苯 为溶剂， 反应 1.0h， 生成 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(benzothiophene-5-carboxamido)morphinan
  参考文献：
  名称：

  Application of Bivalent Bioisostere Concept on Design and Discovery of Potent Opioid Receptor Modulators

  摘要：

  Here, we described the structural modification of previously identified it opioid receptor (MOR) antagonist NAN, a 6 alpha-N-7'-indolyl substituted naltrexamine derivative, and its 6 beta-N-2'-indolyl substituted analogue INTA by adopting the concept of "bivalent bioisostere". Three newly prepared opioid ligands, 25 (NBF), 31, and 38, were identified as potent MOR antagonists both in vitro and in vivo. Moreover, these three compounds significantly antagonized DAMGO-induced intracellular calcium flux and displayed varying degrees of inhibition on cAMP production. Furthermore, NBF produced much less significant withdrawal effects than naloxone in morphine-pelleted mice. Molecular modeling studies revealed that these bivalent bioisosteres may adopt similar binding modes in the MOR and the "address" portions of them may have negative or positive allosteric modulation effects on the function of their "message" portions compared with NAN and INTA. Collectively, our successful application of the "bivalent bioisostere concept" identified a promising lead to develop novel therapeutic agents toward opioid use disorder treatments.

  DOI：

  10.1021/acs.jmedchem.9b01767

文献信息

• Application of Bivalent Bioisostere Concept on Design and Discovery of Potent Opioid Receptor Modulators
  作者：Hongguang Ma、Samuel Obeng、Huiqun Wang、Yi Zheng、Mengchu Li、Abdulmajeed M. Jali、David L. Stevens、William L. Dewey、Dana E. Selley、Yan Zhang

  DOI：10.1021/acs.jmedchem.9b01767

  日期：2019.12.26

  Here, we described the structural modification of previously identified it opioid receptor (MOR) antagonist NAN, a 6 alpha-N-7'-indolyl substituted naltrexamine derivative, and its 6 beta-N-2'-indolyl substituted analogue INTA by adopting the concept of "bivalent bioisostere". Three newly prepared opioid ligands, 25 (NBF), 31, and 38, were identified as potent MOR antagonists both in vitro and in vivo. Moreover, these three compounds significantly antagonized DAMGO-induced intracellular calcium flux and displayed varying degrees of inhibition on cAMP production. Furthermore, NBF produced much less significant withdrawal effects than naloxone in morphine-pelleted mice. Molecular modeling studies revealed that these bivalent bioisosteres may adopt similar binding modes in the MOR and the "address" portions of them may have negative or positive allosteric modulation effects on the function of their "message" portions compared with NAN and INTA. Collectively, our successful application of the "bivalent bioisostere concept" identified a promising lead to develop novel therapeutic agents toward opioid use disorder treatments.