Davood Asghar, Iman Maryam, Pouriaiee Hanieh, Shafaroodi Hamed, Akhbari Sepideh, Azimidoost Leila, Imani Erfan, Rahmatpour Somaieh
Department of Medicinal Chemistry, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran.
Department of Pharmaceutics, Faculty of pharmacy, Baqiyatallah University of Medical Sciences, Tehran, Iran.
Iran J Basic Med Sci. 2017 Apr;20(4):430-437. doi: 10.22038/IJBMS.2017.8586.
Phthalimide-based derivatives have anticonvulsant activity like as phenytoin by inhibition of sodium channel. In our previously research we mentioned about some phthalimide derivatives as potent anticonvulsant agents.
Fourteen analogs of 2-substituted phthalimide pharmacophore were synthesized and then were evaluated for the anticonvulsant activities in pentylenetetrazole-induced seizures (PTZ) and maximal electroshock seizure (MES) models.
The screening results showed that all the analogs have the ability to protect against the maximal electroshock and PTZ. The compounds 3 and 9 elevated clonic seizure thresholds at 30 min which were more active than the standard medicine phenytoin. Compounds 3, 6, 7, 11, 13 and 14 with 100% protection were the most potent ones in tonic seizure. The most potent compound in the both PTZ and MES models was compound 3. Using a model of the open pore of sodium channel, all of the compounds were docked. Results of docking showed that the ligands interacted mainly with residues II-S6 of NaV1.2 by making hydrogen bonds and have additional hydrophobic interactions with other domains in the channel's inner pore.
Some of these compounds are more potent than phenytoin simultaneously in the clonic and tonic seizures.
基于邻苯二甲酰亚胺的衍生物通过抑制钠通道具有类似苯妥英钠的抗惊厥活性。在我们之前的研究中，我们提到了一些邻苯二甲酰亚胺衍生物作为有效的抗惊厥剂。
合成了14种2-取代邻苯二甲酰亚胺药效团类似物，然后在戊四氮诱导惊厥（PTZ）和最大电休克惊厥（MES）模型中评估其抗惊厥活性。
筛选结果表明，所有类似物均具有对抗最大电休克和PTZ的能力。化合物3和9在30分钟时提高了阵挛性惊厥阈值，比标准药物苯妥英钠更具活性。在强直性惊厥中，具有100%保护作用的化合物3、6、7、11、13和14是最有效的。在PTZ和MES模型中最有效的化合物是化合物3。使用钠通道开放孔模型，对所有化合物进行对接。对接结果表明，配体主要通过形成氢键与NaV1.2的II-S6残基相互作用，并与通道内孔中的其他结构域有额外的疏水相互作用。
这些化合物中的一些在阵挛性和强直性惊厥中同时比苯妥英钠更有效。
