Evaluation of anticonvulsant and analgesic effects of benzyl- and benzhydryl ureides

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• 作者：Tadeusz Librowski ; Monika Kubacka ; Manuela Meusel ; Silvia Scolari ; Christa E. Mü ; ller ; Michael Gü ; tschow
• 关键词：Ureides ; Anticonvulsant activity ; Analgesic effect ; GABA ; Adenosine receptors ; Benzodiazepine binding site
• 刊名：European Journal of Pharmacology
• 出版年：2007
• 出版时间：22 March 2007
• 年：2007
• 卷：559
• 期：2-3
• 页码：138-149
• 全文大小：484 K

文摘

The anticonvulsant effects of benzyl- and benzhydryl ureides in mice models of seizures (maximal electroshock seizure test, pentylenetetrazol test, picrotoxin-induced seizure test) and the influence on spontaneous locomotor activity has been assessed. Furthermore, the analgesic effect of ureide derivatives was studied in the hot-plate test in mice. Selected compounds were investigated for their in vitro interaction with adenosine receptors as well as the benzodiazepine binding site of GABA_A receptors. This study demonstrated the strong anticonvulsant activity of several ureides in electrically or chemically induced seizure models, and structure-activity relationships were discussed. 1-Benzyl-3-butyrylurea (9) was found to be equipotent to ethosuximide in the pentylenetetrazol test with regard to the number of attacks as well as the time of the onset of seizures. The ureide 9 also revealed the highest protective activity against seizures in the other models, maximal electroshock seizure and picrotoxin test. Moreover, 1-benzyl-3-butyrylurea was not neurotoxic at doses up to 200 mg/kg. Benzylureides 8–10 showed affinity to the adenosine A₁ receptors at low micromolar concentrations. However, the apparent anticonvulsant activity in different seizure models does not appear to result from direct activation of adenosine A₁ receptors or GABA_A receptors, respectively. In the hot-plate test, the majority of investigated compounds exhibited analgesic activity. Again, compound 9 was superior to the other substances investigated, suggesting a potential therapeutic value of that ureide derivative.