Luszczki Jarogniew J, Karpińska Monika, Matysiak Joanna, Niewiadomy Andrzej
Department of Pathophysiology, Medical University of Lublin, Lublin, Poland; Isobolographic Analysis Laboratory, Institute of Rural Health, Lublin, Poland.
Institute of Industrial Organic Chemistry, Warszawa, Poland.
Pharmacol Rep. 2015 Jun;67(3):588-92. doi: 10.1016/j.pharep.2014.12.008. Epub 2014 Dec 24.
The aim of this study was to perform the anticonvulsant screening test to select some 1,3,4-thiadiazole derivatives that could offer a distinct protection against maximal electroshock (MES)-induced seizures in mice.
The screening test was performed for 13 tested compounds administered intraperitoneally (ip) in a constant dose of 300 mg/kg at various pretreatment times (i.e., 15, 30, 60 and 120 min) before the MES test. Additionally, the active compounds in the screening test were subsequently subjected to the MES test that allowed determination of their median effective doses (ED50 values).
Only 2 out of 13 tested 1,3,4-thiadiazole derivatives i.e., 5-butyl-; and 5-heptyl-substituted in the heterocyclic ring 1,3,4-thiadiazoles produced a distinct protection against MES-induced tonic seizures in mice. Time-course and dose-response effects revealed that 5-butyl-2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole produced its maximum anticonvulsant action at 15 min after its ip administration to mice. In contrast, 5-heptyl-2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole exerted the maximum anticonvulsant action at 60 min after its ip administration to mice. The ED50 values for 5-butyl-2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole ranged between 247 and >500 mg/kg, whereas those for 5-heptyl-2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole ranged between 233 and >500 mg/kg.
5-Butyl-2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole and 5-heptyl-2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole could become potentially favorable antiepileptic drugs, if the results from this study were to be extrapolated into clinical settings.
本研究的目的是进行抗惊厥筛选试验，以选择一些对小鼠最大电休克（MES）诱导的癫痫发作具有显著保护作用的1,3,4 -噻二唑衍生物。
对13种受试化合物进行筛选试验，在MES试验前不同预处理时间（即15、30、60和120分钟）以300mg/kg的恒定剂量腹腔注射（ip）。此外，筛选试验中的活性化合物随后进行MES试验，以确定其半数有效剂量（ED50值）。
13种受试的1,3,4 -噻二唑衍生物中只有2种，即杂环1,3,4 -噻二唑上5 -丁基 - 和5 -庚基取代的衍生物对小鼠MES诱导的强直性癫痫发作具有显著保护作用。时程和剂量反应效应表明，5 -丁基 - 2 -（2,4 -二羟基苯基）-1,3,4 -噻二唑在腹腔注射给小鼠后15分钟产生最大抗惊厥作用。相比之下，5 -庚基 - 2 -（2,4 -二羟基苯基）-1,3,4 -噻二唑在腹腔注射给小鼠后60分钟发挥最大抗惊厥作用。5 -丁基 - 2 -（2,4 -二羟基苯基）-1,3,4 -噻二唑的ED50值在247至>500mg/kg之间，而5 -庚基 - 2 -（2,4 -二羟基苯基）-1,3,4 -噻二唑的ED50值在233至>500mg/kg之间。
如果本研究结果外推至临床情况，5 -丁基 - 2 -（2,4 -二羟基苯基）-1,3,4 -噻二唑和5 -庚基 - 2 -（2,4 -二羟基苯基）-1,3,4 -噻二唑可能成为潜在的有利抗癫痫药物。
