4-[1-(3-methoxyphenyl)piperazin-4-yl]cyclohexylamine | 849411-59-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 4-[1-(3-methoxyphenyl)piperazin-4-yl]cyclohexylamine
• 英文别名: 4-[4-(3-Methoxyphenyl)piperazin-1-yl]cyclohexan-1-amine
• CAS: 849411-59-2
• 化学式: C₁₇H₂₇N₃O
• 分子量: 289.421
• InChiKey: RACBPSBYXDVOGJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  41.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-[1-(3-methoxyphenyl)piperazin-4-yl]cyclohexylamine 在 sodium acetate 、 乙酸酐 作用下， 以 xylene 为溶剂， 反应 10.0h， 生成 trans-1-(3-methoxyphenyl)-4-(4-succinimidocyclohexyl)piperazine
  参考文献：
  名称：

  1-Aryl-4-(4-succinimidobutyl)piperazines and their conformationally constrained analogues: synthesis, binding to serotonin (5-HT1A, 5-HT2A, 5-HT7), α1-adrenergic, and dopaminergic D2 receptors, and in vivo 5-HT1A functional characteristics

  摘要：

  Starting with the structure of potent 5-HT1A ligands, that is, MM77 [1-(2-methoxyphenyl)-4-(4-succinimidobutyl)piperazine, 4] and its constrained version 5 (MP349), previously obtained in our laboratory, a series of their direct analogues with differently substituted aromatic ring (R = H, m-Cl, m-CF3, m-OCH3, p-OCH3) were synthesized. The flexible and the corresponding 1e,4e-disubstituted cyclohexane derivatives were designed in order to investigate the influence of rigidification on 5-HT1A affinity, selectivity for 5-HT2A, 5-HT7, D-1, and D-2 binding sites and functional profile at pre- and postsynaptic 5-HT1A receptors. The new compounds 19-25 were found to be highly active 5-HT1A receptor ligands (K-i = 4-44 nM) whereas their affinity for other receptors was: either significantly decreased after rigidification (5-HT7) or controlled by substituents in the aromatic ring (alpha(1)), or influenced by both those structural modifications (5-HT2A), or very low (D-2, K-i = 5.3-31 mu M). Since a distinct disfavor towards rigid compounds was observed for 5-HT7 receptors only, it seems that the bioactive conformation of chain derivatives at those sites should differ from the extended one.Several in vivo models were used to asses functional activity of 19-25 at pre- (hypothermia in mice) and postsynaptic 5-HT1A receptors (lower lip retraction in rats and serotonin syndrome in reserpinized rats). Unlike the parent antagonists 4 and 5, all the new derivatives tested were classified as partial agonists with different potency, however, similar effects were observed within pairs (flexible and rigid) of the analogues. The obtained results indicated that substitution in the aromatic ring, but not spacer rigidification, controls the 5-HT1A functional activity of the investigated compounds. Moreover, an o-methoxy substituent in the structure of 5 seems to be necessary for its full antagonistic properties. Of all the new compounds studied, trans-4-(4-succinimidocyclohexyl)-1-(3-trifluoromethylphenyl)piperazine 24 was the most potent 5-HT1A receptor ligand in vitro (Ki = 4 nM) and in vivo, with at least 100-fold selectivity for the other receptors tested. (c) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.12.041
• 作为产物：
  描述：

  4-[1-(3-methoxyphenyl)piperazin-4-yl]cyclohexanone oxime 在 sodium 作用下， 以 正丁醇 为溶剂， 以64%的产率得到4-[1-(3-methoxyphenyl)piperazin-4-yl]cyclohexylamine
  参考文献：
  名称：

  1-Aryl-4-(4-succinimidobutyl)piperazines and their conformationally constrained analogues: synthesis, binding to serotonin (5-HT1A, 5-HT2A, 5-HT7), α1-adrenergic, and dopaminergic D2 receptors, and in vivo 5-HT1A functional characteristics

  摘要：

  Starting with the structure of potent 5-HT1A ligands, that is, MM77 [1-(2-methoxyphenyl)-4-(4-succinimidobutyl)piperazine, 4] and its constrained version 5 (MP349), previously obtained in our laboratory, a series of their direct analogues with differently substituted aromatic ring (R = H, m-Cl, m-CF3, m-OCH3, p-OCH3) were synthesized. The flexible and the corresponding 1e,4e-disubstituted cyclohexane derivatives were designed in order to investigate the influence of rigidification on 5-HT1A affinity, selectivity for 5-HT2A, 5-HT7, D-1, and D-2 binding sites and functional profile at pre- and postsynaptic 5-HT1A receptors. The new compounds 19-25 were found to be highly active 5-HT1A receptor ligands (K-i = 4-44 nM) whereas their affinity for other receptors was: either significantly decreased after rigidification (5-HT7) or controlled by substituents in the aromatic ring (alpha(1)), or influenced by both those structural modifications (5-HT2A), or very low (D-2, K-i = 5.3-31 mu M). Since a distinct disfavor towards rigid compounds was observed for 5-HT7 receptors only, it seems that the bioactive conformation of chain derivatives at those sites should differ from the extended one.Several in vivo models were used to asses functional activity of 19-25 at pre- (hypothermia in mice) and postsynaptic 5-HT1A receptors (lower lip retraction in rats and serotonin syndrome in reserpinized rats). Unlike the parent antagonists 4 and 5, all the new derivatives tested were classified as partial agonists with different potency, however, similar effects were observed within pairs (flexible and rigid) of the analogues. The obtained results indicated that substitution in the aromatic ring, but not spacer rigidification, controls the 5-HT1A functional activity of the investigated compounds. Moreover, an o-methoxy substituent in the structure of 5 seems to be necessary for its full antagonistic properties. Of all the new compounds studied, trans-4-(4-succinimidocyclohexyl)-1-(3-trifluoromethylphenyl)piperazine 24 was the most potent 5-HT1A receptor ligand in vitro (Ki = 4 nM) and in vivo, with at least 100-fold selectivity for the other receptors tested. (c) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.12.041

文献信息

• 1-Aryl-4-(4-succinimidobutyl)piperazines and their conformationally constrained analogues: synthesis, binding to serotonin (5-HT1A, 5-HT2A, 5-HT7), α1-adrenergic, and dopaminergic D2 receptors, and in vivo 5-HT1A functional characteristics
  作者：Andrzej J. Bojarski、Maria H. Paluchowska、Beata Duszyńska、Aleksandra Kłodzińska、Ewa Tatarczyńska、Ewa Chojnacka-Wójcik

  DOI：10.1016/j.bmc.2004.12.041

  日期：2005.3

  Starting with the structure of potent 5-HT1A ligands, that is, MM77 [1-(2-methoxyphenyl)-4-(4-succinimidobutyl)piperazine, 4] and its constrained version 5 (MP349), previously obtained in our laboratory, a series of their direct analogues with differently substituted aromatic ring (R = H, m-Cl, m-CF3, m-OCH3, p-OCH3) were synthesized. The flexible and the corresponding 1e,4e-disubstituted cyclohexane derivatives were designed in order to investigate the influence of rigidification on 5-HT1A affinity, selectivity for 5-HT2A, 5-HT7, D-1, and D-2 binding sites and functional profile at pre- and postsynaptic 5-HT1A receptors. The new compounds 19-25 were found to be highly active 5-HT1A receptor ligands (K-i = 4-44 nM) whereas their affinity for other receptors was: either significantly decreased after rigidification (5-HT7) or controlled by substituents in the aromatic ring (alpha(1)), or influenced by both those structural modifications (5-HT2A), or very low (D-2, K-i = 5.3-31 mu M). Since a distinct disfavor towards rigid compounds was observed for 5-HT7 receptors only, it seems that the bioactive conformation of chain derivatives at those sites should differ from the extended one.Several in vivo models were used to asses functional activity of 19-25 at pre- (hypothermia in mice) and postsynaptic 5-HT1A receptors (lower lip retraction in rats and serotonin syndrome in reserpinized rats). Unlike the parent antagonists 4 and 5, all the new derivatives tested were classified as partial agonists with different potency, however, similar effects were observed within pairs (flexible and rigid) of the analogues. The obtained results indicated that substitution in the aromatic ring, but not spacer rigidification, controls the 5-HT1A functional activity of the investigated compounds. Moreover, an o-methoxy substituent in the structure of 5 seems to be necessary for its full antagonistic properties. Of all the new compounds studied, trans-4-(4-succinimidocyclohexyl)-1-(3-trifluoromethylphenyl)piperazine 24 was the most potent 5-HT1A receptor ligand in vitro (Ki = 4 nM) and in vivo, with at least 100-fold selectivity for the other receptors tested. (c) 2004 Elsevier Ltd. All rights reserved.