(-)-N-propyl-3-O-[(trifluoromethyl)sulfonyl]normorphine

• 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: (-)-N-propyl-3-O-[(trifluoromethyl)sulfonyl]normorphine
• 英文别名: [(4R,4aR,7S,7aR,12bS)-7-hydroxy-3-propyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl] trifluoromethanesulfonate
• 化学式: C₂₀H₂₂F₃NO₅S
• 分子量: 445.46
• InChiKey: PKQCOLUXNRPHSC-LEPYJNQMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  84.4
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (-)-N-propyl-3-O-[(trifluoromethyl)sulfonyl]normorphine 在 甲烷磺酸 作用下， 以 乙醚 、 氯仿 为溶剂， 反应 9.0h， 生成 Trifluoro-methanesulfonic acid (R)-11-methoxy-6-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-10-yl ester
  参考文献：
  名称：

  10-Substituted 11-Oxygenated (R)-Aporphines:  Synthesis, Pharmacology, and Modeling of 5-HT_1A Receptor Interactions

  摘要：

  Derivatives of the selective serotonin 5-HT1A receptor agonist (R)-11-hydroxy-10-methylaporphine (2) having various substituents in the C10-position or at the nitrogen have been synthesized from natural morphine or 6-O-acetylcodeine, respectively. The C10-substituents were introduced using efficient Stille or Suzuki cross-coupling reactions. The compounds were evaluated for their affinities to 5-HT1A and dopamine (DA) D-1 and D-2A receptors in vitro. All compounds tested displayed low (micromolar) affinities to D-1 and D-2A receptors. In addition, changes in steric bulk and/or electronic properties of the C10-substituent as compared to a C10-methyl group, as well as substitution of the N-methyl group for a hydrogen or a larger N-alkyl group, produced a marked decrease in the affinities to 5-HT1A receptors. Selected compounds that displayed moderate to high affinities to 5-HT1A receptors were evaluated for their ability to stimulate 5-HT1A receptors in vivo. The evaluated compounds behaved as agonists at 5-HT1A receptors, except for the N-propyl analogue of 2, (R)-11-hydroxy-10-methyl-N-propylnoraporphine (23), which displayed weak DA receptor agonism at the doses tested. Hence, the substitution pattern of 2 (a C10-methyl, a C11-hydroxy, and an N-methyl group) appears to be optimal for potent interaction of 10,11-disubstituted (R)-aporphines with 5-HT1A receptors. Modeling of ligand-5-HT1A receptor interactions was performed in an attempt to rationalize the observed affinity data. The binding site model suggests the presence of a ''methyl pocket'' in the 5-HT1A receptor binding site. The C11-methoxy-substituted aporphines appear to have a different binding mode compared to 2, implying a different accessibility of these compounds to the ''methyl pocket''.

  DOI：

  10.1021/jm960188q
• 作为产物：
  描述：

  去甲可待因 在 sodium tetrahydroborate 、 sodium acetate 、 三溴化硼 、 potassium carbonate 、 溶剂黄146 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 (-)-N-propyl-3-O-[(trifluoromethyl)sulfonyl]normorphine
  参考文献：
  名称：

  10-Substituted 11-Oxygenated (R)-Aporphines:  Synthesis, Pharmacology, and Modeling of 5-HT_1A Receptor Interactions

  摘要：

  Derivatives of the selective serotonin 5-HT1A receptor agonist (R)-11-hydroxy-10-methylaporphine (2) having various substituents in the C10-position or at the nitrogen have been synthesized from natural morphine or 6-O-acetylcodeine, respectively. The C10-substituents were introduced using efficient Stille or Suzuki cross-coupling reactions. The compounds were evaluated for their affinities to 5-HT1A and dopamine (DA) D-1 and D-2A receptors in vitro. All compounds tested displayed low (micromolar) affinities to D-1 and D-2A receptors. In addition, changes in steric bulk and/or electronic properties of the C10-substituent as compared to a C10-methyl group, as well as substitution of the N-methyl group for a hydrogen or a larger N-alkyl group, produced a marked decrease in the affinities to 5-HT1A receptors. Selected compounds that displayed moderate to high affinities to 5-HT1A receptors were evaluated for their ability to stimulate 5-HT1A receptors in vivo. The evaluated compounds behaved as agonists at 5-HT1A receptors, except for the N-propyl analogue of 2, (R)-11-hydroxy-10-methyl-N-propylnoraporphine (23), which displayed weak DA receptor agonism at the doses tested. Hence, the substitution pattern of 2 (a C10-methyl, a C11-hydroxy, and an N-methyl group) appears to be optimal for potent interaction of 10,11-disubstituted (R)-aporphines with 5-HT1A receptors. Modeling of ligand-5-HT1A receptor interactions was performed in an attempt to rationalize the observed affinity data. The binding site model suggests the presence of a ''methyl pocket'' in the 5-HT1A receptor binding site. The C11-methoxy-substituted aporphines appear to have a different binding mode compared to 2, implying a different accessibility of these compounds to the ''methyl pocket''.

  DOI：

  10.1021/jm960188q

文献信息

• 10-Substituted 11-Oxygenated (<i>R</i>)-Aporphines:  Synthesis, Pharmacology, and Modeling of 5-HT_1A Receptor Interactions
  作者：Martin H. Hedberg、Johanna M. Jansen、Gunnar Nordvall、Stephan Hjorth、Lena Unelius、Anette M. Johansson

  DOI：10.1021/jm960188q

  日期：1996.1.1

  Derivatives of the selective serotonin 5-HT1A receptor agonist (R)-11-hydroxy-10-methylaporphine (2) having various substituents in the C10-position or at the nitrogen have been synthesized from natural morphine or 6-O-acetylcodeine, respectively. The C10-substituents were introduced using efficient Stille or Suzuki cross-coupling reactions. The compounds were evaluated for their affinities to 5-HT1A and dopamine (DA) D-1 and D-2A receptors in vitro. All compounds tested displayed low (micromolar) affinities to D-1 and D-2A receptors. In addition, changes in steric bulk and/or electronic properties of the C10-substituent as compared to a C10-methyl group, as well as substitution of the N-methyl group for a hydrogen or a larger N-alkyl group, produced a marked decrease in the affinities to 5-HT1A receptors. Selected compounds that displayed moderate to high affinities to 5-HT1A receptors were evaluated for their ability to stimulate 5-HT1A receptors in vivo. The evaluated compounds behaved as agonists at 5-HT1A receptors, except for the N-propyl analogue of 2, (R)-11-hydroxy-10-methyl-N-propylnoraporphine (23), which displayed weak DA receptor agonism at the doses tested. Hence, the substitution pattern of 2 (a C10-methyl, a C11-hydroxy, and an N-methyl group) appears to be optimal for potent interaction of 10,11-disubstituted (R)-aporphines with 5-HT1A receptors. Modeling of ligand-5-HT1A receptor interactions was performed in an attempt to rationalize the observed affinity data. The binding site model suggests the presence of a ''methyl pocket'' in the 5-HT1A receptor binding site. The C11-methoxy-substituted aporphines appear to have a different binding mode compared to 2, implying a different accessibility of these compounds to the ''methyl pocket''.