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Bioorg Chem ; 106: 104504, 2021 01.
Article in English | MEDLINE | ID: mdl-33279247

ABSTRACT

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).


Subject(s)
Anticonvulsants/pharmacology , Benzodiazepines/pharmacology , Receptors, GABA-A/chemistry , Seizures/drug therapy , Triazoles/pharmacology , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Benzodiazepines/chemical synthesis , Benzodiazepines/chemistry , Binding, Competitive/drug effects , Dose-Response Relationship, Drug , Hydrophobic and Hydrophilic Interactions , Male , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry
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