5'-(4-chlorophenyl)-6,7-didehydro-3,14-dihydroxy-4,5α-epoxy-17-methylpyrido[2',3':6,7]morphinan

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 吗啡烷
• 英文名称: 5'-(4-chlorophenyl)-6,7-didehydro-3,14-dihydroxy-4,5α-epoxy-17-methylpyrido[2',3':6,7]morphinan
• 英文别名: 6-(4-chlorophenyl)-19-methyl-(2S,10R)-11-oxa-8,19-diazahexacyclo[10.9.1.01,10.02,18.04,9.016,22]docosa-4(9),5,7,12,14,16(22)-hexaene-2,13-diol；(1S,2S,10R)-6-(4-chlorophenyl)-19-methyl-11-oxa-8,19-diazahexacyclo[10.9.1.01,10.02,18.04,9.016,22]docosa-4(9),5,7,12,14,16(22)-hexaene-2,13-diol
• 化学式: C₂₆H₂₃ClN₂O₃
• 分子量: 446.933
• InChiKey: YMQBQNZSHDBDTL-OOGIKFLQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  32
• 可旋转键数：
  1
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  65.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5'-(4-chlorophenyl)-6,7-didehydro-3,14-dihydroxy-4,5α-epoxy-17-methylpyrido[2',3':6,7]morphinan 在 三溴化硼 、 sodium hydride 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 1.33h， 生成 (1S,2S,10R)-6-(4-chlorophenyl)-19-methyl-2-phenylmethoxy-11-oxa-8,19-diazahexacyclo[10.9.1.01,10.02,18.04,9.016,22]docosa-4(9),5,7,12,14,16(22)-hexaen-13-ol
  参考文献：
  名称：

  14-Alkoxy- and 14-Acyloxypyridomorphinans: μ Agonist/δ Antagonist Opioid Analgesics with Diminished Tolerance and Dependence Side Effects

  摘要：

  In the search for opioid ligands with mixed functional activity, a series of 5'-(4-chlorophenyl)-4,5 alpha-epoxypyridomorphinans possessing alkoxy or acyloxy groups at C-14 was synthesized and evaluated. In this series, the affinity and functional activity of the ligands were found to be influenced by the nature of the substituent at C-14 as well as by the substituent at N-17. Whereas the incorporation of a 3-phenylpropoxy group at C-14 on N-methylpyridomorhinan gave a dual MOR agonist/DOR agonist 17h, its incorporation on N-cyclopropylmethylpyridomorphinan gave a MOR agonist/DOR antagonist 17d. Interestingly, 17d, in contrast to 17h, did not produce tolerance or dependence effects upon prolonged treatment in cells expressing MOR and DOR. Moreover, 17d displayed greatly diminished analgesic tolerance as compared to morphine upon repeated administration, thus supporting the hypothesis that ligands with MOR agonist/DOR antagonist functional activity could emerge as novel analgesics devoid of tolerance, dependence, and related side effects.

  DOI：

  10.1021/jm300686p
• 作为产物：
  描述：

  盐酸羟可待酮 在 ammonium acetate 、 三溴化硼 、 溶剂黄146 作用下， 以 二氯甲烷 为溶剂， 反应 22.0h， 生成 5'-(4-chlorophenyl)-6,7-didehydro-3,14-dihydroxy-4,5α-epoxy-17-methylpyrido[2',3':6,7]morphinan
  参考文献：
  名称：

  在纳洛酮，羟吗啡酮和氢吗啡酮的吡啶并吗啡喃中鉴定具有混合的微激动剂/δ拮抗剂活性的阿片样物质配体[对氢吗啡酮的校正]。

  摘要：

  合成了一系列衍生自纳洛酮，羟吗啡酮和氢吗啡酮（7a-k）的吡啶基吗啡喃，并使用放射性配体结合测定法评估了在脑膜中阿片样物质δ，微和κ受体上的结合亲和力，并在体外使用[[ 35）S]GTP-γ-S在脑组织中的结合测定以及使用豚鼠回肠（GPI）和小鼠输精管（MVD）平滑肌制备物的生物测定。具有羟吗啡酮和氢吗啡酮骨架的吡啶环未取代的吡啶基吗啡喃在微和δ受体上显示出几乎相等的结合亲和力。它们在κ位点的亲和力比它们在微位点和δ位点的结合亲和力小近10倍。在5'处引入芳基取代基 吡啶环上的α-位改善了δ位点的结合亲和力，同时降低了微位点的结合亲和力。几乎所有在吗啡喃部分的17位具有N-甲基，在吗啡喃部分的14位具有或不具有羟基的配体在微受体上均表现出激动剂活性，具有不同的效能和功效。在[（35）S]GTP-γ-S结合试验中，大多数这些吡啶基吗啡喃在δ和κ受体上没有任何显着的激动剂活性，但在δ受体上表现

  DOI：

  10.1021/jm030311v

文献信息

• Identification of Opioid Ligands Possessing Mixed μ Agonist/δ Antagonist Activity among Pyridomorphinans Derived from Naloxone, Oxymorphone, and Hydropmorphone
  作者：Subramaniam Ananthan、Naveen K. Khare、Surendra K. Saini、Lainne E. Seitz、Jeffrey L. Bartlett、Peg Davis、Christina M. Dersch、Frank Porreca、Richard B. Rothman、Edward J. Bilsky

  DOI：10.1021/jm030311v

  日期：2004.3.1

  profile of mixed micro agonist/delta antagonist activity in vitro and in vivo. In a repeated administration paradigm in which the standard micro agonist morphine produces significant tolerance, repeated administration of the micro agonist/delta antagonist ligand 7h produced no tolerance. These results indicate that appropriate molecular manipulations of the morphinan templates could provide ligands with

  合成了一系列衍生自纳洛酮，羟吗啡酮和氢吗啡酮（7a-k）的吡啶基吗啡喃，并使用放射性配体结合测定法评估了在脑膜中阿片样物质δ，微和κ受体上的结合亲和力，并在体外使用[[ 35）S]GTP-γ-S在脑组织中的结合测定以及使用豚鼠回肠（GPI）和小鼠输精管（MVD）平滑肌制备物的生物测定。具有羟吗啡酮和氢吗啡酮骨架的吡啶环未取代的吡啶基吗啡喃在微和δ受体上显示出几乎相等的结合亲和力。它们在κ位点的亲和力比它们在微位点和δ位点的结合亲和力小近10倍。在5'处引入芳基取代基 吡啶环上的α-位改善了δ位点的结合亲和力，同时降低了微位点的结合亲和力。几乎所有在吗啡喃部分的17位具有N-甲基，在吗啡喃部分的14位具有或不具有羟基的配体在微受体上均表现出激动剂活性，具有不同的效能和功效。在[（35）S]GTP-γ-S结合试验中，大多数这些吡啶基吗啡喃在δ和κ受体上没有任何显着的激动剂活性，但在δ受体上表现
• 14-Alkoxy- and 14-Acyloxypyridomorphinans: μ Agonist/δ Antagonist Opioid Analgesics with Diminished Tolerance and Dependence Side Effects
  作者：Subramaniam Ananthan、Surendra K. Saini、Christina M. Dersch、Heng Xu、Nicholas McGlinchey、Denise Giuvelis、Edward J. Bilsky、Richard B. Rothman

  DOI：10.1021/jm300686p

  日期：2012.10.11

  In the search for opioid ligands with mixed functional activity, a series of 5'-(4-chlorophenyl)-4,5 alpha-epoxypyridomorphinans possessing alkoxy or acyloxy groups at C-14 was synthesized and evaluated. In this series, the affinity and functional activity of the ligands were found to be influenced by the nature of the substituent at C-14 as well as by the substituent at N-17. Whereas the incorporation of a 3-phenylpropoxy group at C-14 on N-methylpyridomorhinan gave a dual MOR agonist/DOR agonist 17h, its incorporation on N-cyclopropylmethylpyridomorphinan gave a MOR agonist/DOR antagonist 17d. Interestingly, 17d, in contrast to 17h, did not produce tolerance or dependence effects upon prolonged treatment in cells expressing MOR and DOR. Moreover, 17d displayed greatly diminished analgesic tolerance as compared to morphine upon repeated administration, thus supporting the hypothesis that ligands with MOR agonist/DOR antagonist functional activity could emerge as novel analgesics devoid of tolerance, dependence, and related side effects.