Trifluoro-methanesulfonic acid (R)-11-methoxy-6-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-10-yl ester | 179952-74-0

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 阿朴菲
• 英文名称: Trifluoro-methanesulfonic acid (R)-11-methoxy-6-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-10-yl ester
• 英文别名: [(6aR)-11-methoxy-6-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-10-yl] trifluoromethanesulfonate
• CAS: 179952-74-0
• 化学式: C₂₁H₂₂F₃NO₄S
• 分子量: 441.471
• InChiKey: VFZQJEHONJLING-MRXNPFEDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  64.2
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  Trifluoro-methanesulfonic acid (R)-11-methoxy-6-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-10-yl ester 在 bis-triphenylphosphine-palladium(II) chloride 、 甲酸 、 三正丁胺 、 1,3-双(二苯基膦)丙烷 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 (R)-(-)-11-methoxy-N-n-propylnoraporphine
  参考文献：
  名称：

  11-Substituted (R)-Aporphines:  Synthesis, Pharmacology, and Modeling of D_2A and 5-HT_1A Receptor Interactions

  摘要：

  A series of C11-substituted (R)-aporphines and C11-oxygenated (R)-noraporphines has been synthesized and evaluated for central serotonergic and dopaminergic effects in vitro and in vivo. The various C11-substituents were introduced using efficient nickel- and palladium-catalyzed reactions of the corresponding triflate (R)-11-[[(trifluoromethyl)sulfonyl]oxy] aporphine (6), Several compounds display high affinity to serotonin 5-HT1A receptors in spite of major differences in steric bulk and electronic properties of the various C11-substituents. A change of the N-methyl group of the nonselective 3 to H [23, (R)-11-hydroxynoraporphine] or propyl [2, (R)-11-hydroxy-N-propylnoraporphine] increases the selectivity for 5-HT1A receptors (100-fold) and dopamine D-2A receptors (3-fold), respectively. Compounds 3 and 23 have similar affinities to 5-HT1A receptors, whereas the propyl substituent of 2 not only enhances the selectivity for D-2A receptors but also increases the D-2A affinity. Modeling of ligand-receptor binding site interactions yielded an interaction site model for the 5-HT1A receptor that describes a gradual change in binding mode for C11-hydroxy, -methoxy-, and -phenyl-substituted derivatives. Hydrogen bonding is hereby gradually replaced by van der Waals interactions involving a relatively large lipophilic pocket. The derived D-2A receptor model can accommodate both the N-propyl substituent of 2 and the C11-ethyl substituent of 11 [(R)-11-ethylaporphine].

  DOI：

  10.1021/jm960189i
• 作为产物：
  描述：

  去甲可待因 在 sodium tetrahydroborate 、 甲烷磺酸 、 sodium acetate 、 三溴化硼 、 potassium carbonate 、 溶剂黄146 、 三乙胺 作用下， 以 乙醚 、 二氯甲烷 、 氯仿 为溶剂， 反应 12.0h， 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

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''.
• 11-Substituted (<i>R</i>)-Aporphines:  Synthesis, Pharmacology, and Modeling of D_2A and 5-HT_1A Receptor Interactions
  作者：Martin H. Hedberg、Tero Linnanen、Johanna M. Jansen、Gunnar Nordvall、Stephan Hjorth、Lena Unelius、Anette M. Johansson

  DOI：10.1021/jm960189i

  日期：1996.1.1

  A series of C11-substituted (R)-aporphines and C11-oxygenated (R)-noraporphines has been synthesized and evaluated for central serotonergic and dopaminergic effects in vitro and in vivo. The various C11-substituents were introduced using efficient nickel- and palladium-catalyzed reactions of the corresponding triflate (R)-11-[[(trifluoromethyl)sulfonyl]oxy] aporphine (6), Several compounds display high affinity to serotonin 5-HT1A receptors in spite of major differences in steric bulk and electronic properties of the various C11-substituents. A change of the N-methyl group of the nonselective 3 to H [23, (R)-11-hydroxynoraporphine] or propyl [2, (R)-11-hydroxy-N-propylnoraporphine] increases the selectivity for 5-HT1A receptors (100-fold) and dopamine D-2A receptors (3-fold), respectively. Compounds 3 and 23 have similar affinities to 5-HT1A receptors, whereas the propyl substituent of 2 not only enhances the selectivity for D-2A receptors but also increases the D-2A affinity. Modeling of ligand-receptor binding site interactions yielded an interaction site model for the 5-HT1A receptor that describes a gradual change in binding mode for C11-hydroxy, -methoxy-, and -phenyl-substituted derivatives. Hydrogen bonding is hereby gradually replaced by van der Waals interactions involving a relatively large lipophilic pocket. The derived D-2A receptor model can accommodate both the N-propyl substituent of 2 and the C11-ethyl substituent of 11 [(R)-11-ethylaporphine].