[4-(3-nitro-2-pyridyl)piperazin-1-yl]-(2-phenylphenyl)-methanone

• 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-(3-nitro-2-pyridyl)piperazin-1-yl]-(2-phenylphenyl)-methanone
• 英文别名: [4-(3-Nitropyridin-2-yl)piperazin-1-yl]-(2-phenylphenyl)methanone；[4-(3-nitropyridin-2-yl)piperazin-1-yl]-(2-phenylphenyl)methanone
• 化学式: C₂₂H₂₀N₄O₃
• 分子量: 388.426
• InChiKey: JYISLSJPMUEIFV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  82.3
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1-(3-硝基吡啶-2-基)哌嗪 、 二氢-3-(异十二碳烯基)呋喃-2,5-二酮 在 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 以53%的产率得到[4-(3-nitro-2-pyridyl)piperazin-1-yl]-(2-phenylphenyl)-methanone
  参考文献：
  名称：

  Insights into the interaction of negative allosteric modulators with the metabotropic glutamate receptor 5: Discovery and computational modeling of a new series of ligands with nanomolar affinity

  摘要：

  Metabotropic glutamate receptor 5 (mGlu(5)) is a biological target implicated in major neurological and psychiatric disorders. In the present study, we have investigated structural determinants of the interaction of negative allosteric modulators (NAMs) with the seven-transmembrane (7TM) domain of mGlu(5). A homology model of the 7TM receptor domain built on the crystal structure of the mGlu(1) template was obtained, and the binding modes of known NAMs, namely MPEP and fenobam, were investigated by docking and molecular dynamics simulations. The results were validated by comparison with mutagenesis data available in the literature for these two ligands, and subsequently corroborated by the recently described mGlu(5) crystal structure. Moreover, a new series of NAMs was synthesized and tested, providing compounds with nanomolar affinity. Several structural modifications were sequentially introduced with the aim of identifying structural features important for receptor binding. The synthesized NAMs were docked in the validated homology model and binding modes were used to interpret and discuss structure-activity relationships within this new series of compounds. Finally, the models of the interaction of NAMs with mGlu(5) were extended to include important non-aryl alkyne mGlu(5) NAMs taken from the literature. Overall, the results provide useful insights into the molecular interaction of negative allosteric modulators with mGlu(5) and may facilitate the design of new modulators for this class of receptors. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.05.008

文献信息

• Insights into the interaction of negative allosteric modulators with the metabotropic glutamate receptor 5: Discovery and computational modeling of a new series of ligands with nanomolar affinity
  作者：Andrew Anighoro、Davide Graziani、Ilaria Bettinelli、Antonio Cilia、Carlo De Toma、Matteo Longhi、Fabio Mangiarotti、Sergio Menegon、Lorenza Pirona、Elena Poggesi、Carlo Riva、Giulio Rastelli

  DOI：10.1016/j.bmc.2015.05.008

  日期：2015.7

  Metabotropic glutamate receptor 5 (mGlu(5)) is a biological target implicated in major neurological and psychiatric disorders. In the present study, we have investigated structural determinants of the interaction of negative allosteric modulators (NAMs) with the seven-transmembrane (7TM) domain of mGlu(5). A homology model of the 7TM receptor domain built on the crystal structure of the mGlu(1) template was obtained, and the binding modes of known NAMs, namely MPEP and fenobam, were investigated by docking and molecular dynamics simulations. The results were validated by comparison with mutagenesis data available in the literature for these two ligands, and subsequently corroborated by the recently described mGlu(5) crystal structure. Moreover, a new series of NAMs was synthesized and tested, providing compounds with nanomolar affinity. Several structural modifications were sequentially introduced with the aim of identifying structural features important for receptor binding. The synthesized NAMs were docked in the validated homology model and binding modes were used to interpret and discuss structure-activity relationships within this new series of compounds. Finally, the models of the interaction of NAMs with mGlu(5) were extended to include important non-aryl alkyne mGlu(5) NAMs taken from the literature. Overall, the results provide useful insights into the molecular interaction of negative allosteric modulators with mGlu(5) and may facilitate the design of new modulators for this class of receptors. (C) 2015 Elsevier Ltd. All rights reserved.