Acid-catalysed hydrolysis and benzodiazepine-like properties of 5-(dialkylamino)- and 5-(alkylthio)-substituted 8-chloro-6-phenyl-6H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepines in mice

The in-vitro and in-vivo hydrolysis of two benzodiazepine compounds has bee n studied to evaluate their in-vivo activity in mice. Compounds RL 218 and RL 236, selected as representative examples of N,N-dia lkyl-8-chloro-6-phenyl-6H-[1,2,4]triazolo[4,3-a](1) and of their 5(alkylthi o) substituted analogues (2), were rapidly hydrolysed to the corresponding 8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a] 3 (RL 214) in aqueous acidic so lution at pH 1 5. This reaction also occurred extensively in mice when comp ounds RL, 218 and RL 236 were given orally but not intraperitoneally. Both compounds were active against pentylenetetrazole-induced lethal convulsions in mice only when administered orally. After administration of pharmacolog ically effective oral doses (ED50, the dose protecting 50% of mice), at the time of assessment of the anti-pentylenetetrazole activity, mean brain con centrations of RL 218 and RL 236 were below the limits of sensitivity of th e analytical procedure whereas brain concentrations of their metabolite RL 214 were comparable with that present after an oral equiactive dose of this compound itself. RL 214 but not RL 218 or RL 236 had in-vitro affinity for brain benzodiazepine receptors. These results indicate that the anticonvulsant activity of RL 218 and RL 23 6 in mice depends essentially on their in-vivo transformation into the comm on active metabolite RL 214 which most probably arises as a result of acid catalysed hydrolysis in the gastric juice.