Synthesis and Evaluation of Pharmacological and Pharmacokinetic Properties of 11H-[1,2,4]Triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones

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Abstract
A series of 2,3-benzodiazepine derivatives has been previously described as noncompetitive AMPA-type glutamate receptor antagonists potentially useful for treatment of epilepsy. To further explore the structure−activity relationships of AMPA antagonists, a series of 11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones (6) was synthesized starting from the corresponding bicyclic 1-aryl-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-ones (2, CFM). The new compounds were found to possess anticonvulsant effects against seizures induced both by means of auditory stimulation in DBA/2 mice and by pentylenetetrazole or maximal electroshock in Swiss mice. In addition, they antagonize the AMPA-induced seizures, and their anticonvulsant activity is reversed by pretreatment with aniracetam, thus suggesting the involvement of AMPA receptors. The pharmacological studies revealed that the 11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones (6) herein reported show anticonvulsant activity comparable to that of their bicyclic precursors. Furthermore, an HPLC study put in evidence that these tricyclic derivatives 6 were converted in vivo into the corresponding 2, the agents likely to be mainly responsible for the anticonvulsant properties observed.