Evaluation of anticonvulsant and analgesic effects of benzyl- and benzhydryl ureides.
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.
Librowski
Tadeusz
T
Department of Pharmacodynamics, Medical College, Jagiellonian University, Medyczna 9, 30-688 Kraków, Poland. mflibrow@cyf-kr.edu.pl
Kubacka
Monika
M
Meusel
Manuela
M
Scolari
Silvia
S
Müller
Christa E
CE
Gütschow
Michael
M
D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001559:Benzhydryl Compounds / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001593:Benzyl Compounds / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001667:Binding, Competitive; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D006358:Hot Temperature; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010433:Pentylenetetrazole; D010852:Picrotoxin; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity
D000700:Analgesics; D000927:Anticonvulsants; D001559:Benzhydryl Compounds; D001593:Benzyl Compounds; D010433:Pentylenetetrazole; D010852:Picrotoxin; D011963:Receptors, GABA-A; D018047:Receptors, Purinergic P1; D014508:Urea