RESUMO
A new series of 5-(2-aryloxy-4-nitrophenyl)-4H-1,2,4-triazoles and 5-(2-aryloxy-3-pyridyl)-4H-1,2,4-triazoles, possessing C-3 thio or alkylthio substituents, was synthesized and evaluated for their benzodiazepine receptor affinity and anti-seizure activity. These analogues revealed similar to significantly superior affinity to GABAA/benzodiazepine receptor complex (IC50 values of 0.04-4.1 nM), relative to diazepam as the reference drug (IC50 value of 2.4 nM). To determine the onset of anti-seizure activity, the time-dependent effectiveness of i.p. administration of compounds on pentylenetetrazole induced seizure threshold was studied and a very good relationship was observed between the lipophilicity (cLogP) and onset of action of studied analogues (r2 = 0.964). The minimum effective dose of the compounds, determined at the time the analogues showed their highest activity, was demonstrated to be 0.025-0.1 mg/kg, relative to diazepam (0.025 mg/kg).
Assuntos
Anticonvulsivantes/farmacologia , Benzodiazepinas/farmacologia , Receptores de GABA-A/química , Convulsões/tratamento farmacológico , Triazóis/farmacologia , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Benzodiazepinas/síntese química , Benzodiazepinas/química , Ligação Competitiva/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interações Hidrofóbicas e Hidrofílicas , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
The new series of 5-(2-phenoxybenzyl)-4H-1,2,4-triazoles, possessing C-3 thio, alkylthio and ethoxy substituents, and 2-amino-5-(2-phenoxybenzyl)-1,3,4-oxadiazoles were designed and synthesized as novel benzodiazepine analogues. Most of them revealed similar to superior binding affinity to the GABAA/benzodiazepine receptor complex, relative to diazepam as the reference drug. Among them, 5-(4-chloro-2-(2-fluorophenoxy)benzyl)-3-benzylthio-4H-1,2,4-triazole (8l) showed the highest affinity (IC50=0.892 nM) relative to diazepam (IC50=2.857 nM) and also showed the most increase in pentylenetetrazole-induced seizure threshold relative to diazepam as the reference drug.