17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{[4'-(2'-methylpyridyl)]carboxamido}morphinan | 1236037-42-5

• 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-{[4'-(2'-methylpyridyl)]carboxamido}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]-2-methylpyridine-4-carboxamide
• CAS: 1236037-42-5
• 化学式: C₂₇H₃₁N₃O₄
• 分子量: 461.561
• InChiKey: ZTGDWDNXGYCMFI-XGTKUTNFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  34
• 可旋转键数：
  4
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  94.9
• 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-6β-{[4'-(2'-methylpyridyl)]carboxamido}morphinan 在 盐酸 作用下， 以 甲醇 为溶剂， 反应 0.5h， 生成 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]-2-methylpyridine-4-carboxamide;hydrochloride
  参考文献：
  名称：

  Structure selectivity relationship studies of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)carboxamido]morphinan derivatives toward the development of the mu opioid receptor antagonists

  摘要：

  Mu opioid receptor antagonists have been applied to target a variety of diseases clinically. The current study is designed to explore the structure selectivity relationship (SSR) of 17-cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 beta-[(4'-pyridyl)carboxamido]morphinan (NAP), a lead compound identified as a selective mu opioid receptor antagonist based on the previous study. Among a series of NAP derivatives synthesized, compounds 6 (NMP) and 9 (NGP) maintained comparable binding affinity, selectivity and efficacy to the lead compound. Particularly, the mu opioid receptor selectivity over kappa opioid receptor of NGP was considerably enhanced compared to that of NAP. Overall, the preliminary SSR supported our original hypothesis that an alternate 'address' domain may exist in the mu opioid receptor, which favors the ligands carrying a hydrogen bond acceptor and an aromatic system to selectively recognize the mu opioid receptor. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2011.06.135
• 作为产物：
  描述：

  纳曲酮 在 盐酸 、 palladium on activated charcoal 、 potassium carbonate 、 1-羟基苯并三唑 、 对甲苯磺酸 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 0.25h， 生成 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{[4'-(2'-methylpyridyl)]carboxamido}morphinan
  参考文献：
  名称：

  17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)carboxamido]morphinan 衍生物作为外周选择性μ阿片受体药物的设计、合成和生物学评价

  摘要：

  外周选择性μ阿片受体（MOR）拮抗剂可以减轻阿片类药物引起的便秘（OIC）的症状，而不会影响阿片类药物的镇痛作用。然而，与它们相关的各种不利影响，部分是由于它们相对较低的 MOR 选择性。NAP 是一种6β- N -4'-吡啶基取代的纳曲胺衍生物，以前被鉴定为主要作用于外周神经系统的有效且高度选择性的 MOR 拮抗剂。与之相关的明显腹泻促使设计和合成其类似物以研究其结构-活性关系。其中，化合物8与原始铅相比，显示出改善的药理学特征，主要作用于外周，同时增加吗啡颗粒小鼠的肠蠕动（ED 50 = 0.03 mg/kg）。与原始铅相比，ED 50的轻微下降被未观察到的不利影响很好地补偿了。因此，该化合物似乎是开发针对 OIC 的新型治疗剂的更有希望的线索。

  DOI：

  10.1021/jm301247n

文献信息

• Design, Synthesis, and Biological Evaluation of 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)carboxamido]morphinan Derivatives as Peripheral Selective μ Opioid Receptor Agents
  作者：Yunyun Yuan、Orgil Elbegdorj、Jianyang Chen、Shashidhar K. Akubathini、Feng Zhang、David L. Stevens、Irina O. Beletskaya、Krista L. Scoggins、Zhenxian Zhang、Phillip M. Gerk、Dana E. Selley、Hamid I. Akbarali、William L. Dewey、Yan Zhang

  DOI：10.1021/jm301247n

  日期：2012.11.26

  MOR antagonist mainly acting within the peripheral nervous system. The noticeable diarrhea associated with it prompted the design and synthesis of its analogues in order to study its structure–activity relationship. Among them, compound 8 showed improved pharmacological profiles compared to the original lead, acting mainly at peripheral while increasing the intestinal motility in morphine-pelleted mice

  外周选择性μ阿片受体（MOR）拮抗剂可以减轻阿片类药物引起的便秘（OIC）的症状，而不会影响阿片类药物的镇痛作用。然而，与它们相关的各种不利影响，部分是由于它们相对较低的 MOR 选择性。NAP 是一种6β- N -4'-吡啶基取代的纳曲胺衍生物，以前被鉴定为主要作用于外周神经系统的有效且高度选择性的 MOR 拮抗剂。与之相关的明显腹泻促使设计和合成其类似物以研究其结构-活性关系。其中，化合物8与原始铅相比，显示出改善的药理学特征，主要作用于外周，同时增加吗啡颗粒小鼠的肠蠕动（ED 50 = 0.03 mg/kg）。与原始铅相比，ED 50的轻微下降被未观察到的不利影响很好地补偿了。因此，该化合物似乎是开发针对 OIC 的新型治疗剂的更有希望的线索。
• Structure selectivity relationship studies of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)carboxamido]morphinan derivatives toward the development of the mu opioid receptor antagonists
  作者：Yunyun Yuan、Orgil Elbegdorj、Jianyang Chen、Shashidhar K. Akubathini、Irina O. Beletskaya、Dana E. Selley、Yan Zhang

  DOI：10.1016/j.bmcl.2011.06.135

  日期：2011.9

  Mu opioid receptor antagonists have been applied to target a variety of diseases clinically. The current study is designed to explore the structure selectivity relationship (SSR) of 17-cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 beta-[(4'-pyridyl)carboxamido]morphinan (NAP), a lead compound identified as a selective mu opioid receptor antagonist based on the previous study. Among a series of NAP derivatives synthesized, compounds 6 (NMP) and 9 (NGP) maintained comparable binding affinity, selectivity and efficacy to the lead compound. Particularly, the mu opioid receptor selectivity over kappa opioid receptor of NGP was considerably enhanced compared to that of NAP. Overall, the preliminary SSR supported our original hypothesis that an alternate 'address' domain may exist in the mu opioid receptor, which favors the ligands carrying a hydrogen bond acceptor and an aromatic system to selectively recognize the mu opioid receptor. Published by Elsevier Ltd.