Department of Pharmacology, Faculty of Health Sciences, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland.
Department of Clinical Genetics, Faculty of Medicine, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland.
Molecules. 2023 Jul 7;28(13):5287. doi: 10.3390/molecules28135287.
The main aim of the current project was to investigate the effect of the linker size in 4-alkyl-5-aryl-1,2,4-triazole-3-thione derivatives, known as a group of antiepileptic drug candidates, on their affinity towards voltage-gated sodium channels (VGSCs). The rationale of the study was based both on the SAR observations and docking simulations of the interactions between the designed ligands and the binding site of human VGSC. HYDE docking scores, which describe hydrogen bonding, desolvation, and hydrophobic effects, obtained for 5-[(3-chlorophenyl)ethyl]-4-butyl/hexyl-1,2,4-triazole-3-thiones, justified their beneficial sodium channel blocking activity. The results of docking simulations were verified using a radioligand binding assay with [H]batrachotoxin. Unexpectedly, although the investigated triazole-based compounds acted as VGSC ligands, their affinities were lower than those of the respective analogs containing shorter alkyl linkers. Since numerous sodium channel blockers are recognized as antiepileptic agents, the obtained 1,2,4-triazole derivatives were examined for antiepileptic potential using an experimental model of tonic-clonic seizures in mice. Median effective doses (ED) of the compounds examined in MES test reached 96.6 ± 14.8 mg/kg, while their median toxic doses (TD), obtained in the rotarod test, were even as high as 710.5 ± 47.4 mg/kg.
本研究旨在探讨 4-烷基-5-芳基-1,2,4-三唑-3-硫酮衍生物（已知是一组抗癫痫候选药物）中连接子大小对其与电压门控钠离子通道（VGSCs）亲和力的影响。研究的依据是基于设计配体与人类 VGSC 结合位点相互作用的 SAR 观察和对接模拟。对于 5-[(3-氯苯基)乙基]-4-丁基/己基-1,2,4-三唑-3-硫酮获得的 HYDE 对接评分，描述了氢键、去溶剂化和疏水相互作用，证明了它们具有有益的钠通道阻断活性。对接模拟的结果使用 [H]batrachotoxin 放射性配体结合测定法进行了验证。出乎意料的是，尽管研究的三唑基化合物作为 VGSC 配体起作用，但它们的亲和力低于具有较短烷基连接子的相应类似物。由于许多钠离子通道阻滞剂被认为是抗癫痫药物，因此使用小鼠强直-阵挛性癫痫发作的实验模型来检查获得的 1,2,4-三唑衍生物的抗癫痫潜力。在 MES 测试中检查的化合物的中位数有效剂量（ED）达到 96.6±14.8mg/kg，而在旋转棒测试中获得的中位数毒性剂量（TD）甚至高达 710.5±47.4mg/kg。
