Modulation of native GABAA receptor activity by triazolo 1,5-benzodiazepines

Abstract In previous work our group described the synthesis and the activity on rat cerebellum granule cell GABA A receptors of new 1,5-benzodiazepine compounds. Here we are describing the synthesis of new triazolobenzodiazepines (mainly 1,5-benzodiazepine derivatives) and the evaluation of their biological activity in terms of effects on those GABA A receptors. Their effects were compared to those of 1,4-benzodiazepine agonists and some known 1,5-benzodiazepines. The activities were evaluated for the two GABA A receptor populations present in cerebellar granule cells, one mediating phasic inhibition and the other one mediating tonic inhibition. Some of the compounds displayed a profile of agonist at the component mediating phasic inhibition. This agonistic activity was prevented by the benzodiazepine site antagonist flumazenil. Interestingly, the active compounds displayed an agonistic activity at these receptors significantly greater than that of “classical” 1,4-benzodiazepine agonists, such as diazepam, flunitrazepam and alprazolam.