ANTICONVULSANT PROFILE OF THE IMIDAZOQUINAZOLINES NNC 14-0185 AND NNC14-0189 IN RATS AND MICE

The anticonvulsant effects of NNC 14-0185 )-6-fluoro-5-morpholino-imid azo[1,5-a]quinazoline) and NNC 14-0189 4-methyl-1-piperazinyl)-imidazo [1,5-a]quinazoline) in mice and rats were evaluated and compared with those of diazepam, clonazepam and the novel beta-carboline, abecarnil. Following i.p. administration, NNC 14-0185 and NNC 14-0189 prevented audiogenic seizures in DBA/2 mice and the clonic convulsions induced i n mice by pentylenetetrazole, DMCM (methyl 7-dimethoxy-4-ethyl-beta-ca rboline-3-carboxylate), 3-mercaptopropionic acid and a low dose of bic uculline. NNC 14-0185 and NNC 14-0189 prevented seizures induced by pe ntylenetetrazole in rats and were also effective anticonvulsants in am ygdala-kindled rats. In general, the anticonvulsant potencies of NNC 1 4-0185 and NNC 14-0189 were comparable to those of the reference benzo diazepines. However, like abecarnil, they were not effective against t he seizures induced in mice by maximal electroshock and a high dose of bicuculline. The anticonvulsant effects of NNC 14-0185 and NNC 14-018 9 against pentylenetetrazole-induced seizures were apparent within 5 m in of i.p. injection and persisted for at least 2 h. These effects app eared to be mediated by benzodiazepine receptors since they were inhib ited by concurrent administration of flumazenil. Both NNC 14-0185 and NNC 14-0189 showed greater separation between their anticonvulsant and muscle relaxant effects (measured as impaired rotarod performance) th an did diazepam. In this respect, their therapeutic windows were simil ar (NNC 14-0185) to or better (NNC 14-0189) than that of abecarnil. To lerance did not develop to the anticonvulsant effects of NNC 14-0185 a nd NNC 14-0189 over a 4-day test. In comparison, the anticonvulsant ef fects of diazepam and abecarnil were attenuated by repeated drug admin istration. Thus, NNC 14-0185 and NNC 14-0189 have a promising anticonv ulsant and side-effect profile in comparison with diazepam, clonazepam and abecarnil. The potential use of these compounds in the treatment of epilepsy should be explored further.