Design, Synthesis and Protection Against Pentylenetetrazole-induced Seizure of N-aryl Derivatives of the Phthalimide Pharmacophore
Design, Synthesis and Protection Against Pentylenetetrazole-induced Seizure of N-aryl Derivatives of the Phthalimide Pharmacophore
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DOI：
10.2174/157340612802084289
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发表时间：
2012-09-01
影响因子：
2.3
通讯作者：
Iman, Maryam
中科院分区：
文献类型：
--
作者：
Davood, Asghar;Shafaroodi, Hamed;Iman, Maryam
合成了一系列包含邻苯二甲酰亚胺和4-硝基邻苯二甲酰亚胺的N-芳基取代基的化合物，并评价了它们的抗惊厥特性。体内筛选数据表明所有类似物都具有预防戊四唑诱导的癫痫发作的能力。这些化合物在给药后30分钟发挥最大作用。在强直和阵挛性癫痫发作中最有效的化合物是 1-萘基衍生物（化合物 6），它比参考药物苯妥英更活跃。使用Na通道的开孔模型，将这些抗惊厥药停靠在活性位点，并检查与通过诱变鉴定对其结合能重要的残基的关系。对接研究表明，所有化合物 (1-13) 主要通过与通道内孔中的结构域 I 和 II 形成氢键以及额外的疏水相互作用，与 NaV1.2 的残基 II-S6 相互作用。
A series of compounds including N-aryl substituents of phthalimide and 4-nitrophthalimide were synthesized and evaluated for their anticonvulsant properties. The in vivo screening data suggest that all the analogs have the ability to protect against pentylenetetrazole-induced seizures. These compounds exerted their maximal effects 30 min after administration. The most potent compound in both, tonic and clonic seizure was 1-naphthyl derivative (comp. 6), which was more active than the reference drug known as Phenytoin. Using an open pore model of the Na channel, these anticonvulsants were docked in the active site and examined in relation to the residues identified by mutagenesis as important for their binding energies. Docking studies revealed that all compounds (1-13) interacted mainly with residues II-S6 of NaV1.2 by making hydrogen bonds and additional hydrophobic interactions with domain I and II in the channel's inner pore.