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 (2, CFM). The new compounds were found to possess anticonvulsant effects against seizures induced both by means of auditory;stimulation hi 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 mere converted in vivo into the corresponding 2, the agents likely to be mainly responsible for the anticonvulsant properties observed.
Synthesis and evaluation of pharmacological and pharmacokinetic properties of 11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones
De Sarro G;
2000-01-01
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 (2, CFM). The new compounds were found to possess anticonvulsant effects against seizures induced both by means of auditory;stimulation hi 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 mere converted in vivo into the corresponding 2, the agents likely to be mainly responsible for the anticonvulsant properties observed.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.