title: Anticonvulsant profile of the imidazoquinazolines NNC 14-0185 and NNC 14-0189 in rats and mice.
abstract: The anticonvulsant effects of NNC 14-0185 (3-(3-cyclopropyl-5-isoxazolyl)-6-fluoro-5-morpholino-imidazo[1,5- a] quinazoline) and NNC 14-0189 (3-(5-cyclopropyl-1,2, 4-oxadiazol-3-yl)-7-fluoro-5-(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 in mice by pentylenetetrazole, DMCM (methyl 6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate), 3-mercaptopropionic acid and a low dose of bicuculline. NNC 14-0185 and NNC 14-0189 prevented seizures induced by pentylenetetrazole in rats and were also effective anticonvulsants in amygdala-kindled rats. In general, the anticonvulsant potencies of NNC 14-0185 and NNC 14-0189 were comparable to those of the reference benzodiazepines. However, like abecarnil, they were not effective against the seizures induced in mice by maximal electroshock and a high dose of bicuculline. The anticonvulsant effects of NNC 14-0185 and NNC 14-0189 against pentylenetetrazole-induced seizures were apparent within 5 min of i.p. injection and persisted for at least 2 h. These effects appeared to be mediated by benzodiazepine receptors since they were inhibited 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) than did diazepam. In this respect, their therapeutic windows were similar (NNC 14-0185) to or better (NNC 14-0189) than that of abecarnil. Tolerance did not develop to the anticonvulsant effects of NNC 14-0185 and NNC 14-0189 over a 4-day test. In comparison, the anticonvulsant effects of diazepam and abecarnil were attenuated by repeated drug administration. Thus, NNC 14-0185 and NNC 14-0189 have a promising anticonvulsant 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.
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park, Mål-v, Denmark.
authors.forename: H C
authors.initials: HC
authors.lastname: Jackson
authors.forename: H C
authors.initials: HC
authors.lastname: Hansen
authors.forename: M
authors.initials: M
authors.lastname: Kristiansen
authors.forename: P D
authors.initials: PD
authors.lastname: Suzdak
authors.forename: H
authors.initials: H
authors.lastname: Klitgaard
authors.forename: M E
authors.initials: ME
authors.lastname: Judge
authors.forename: M D
authors.initials: MD
authors.lastname: Swedberg
mesh_terms: D000161:Acoustic Stimulation; D000679:Amygdala / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D001640:Bicuculline / Q000009:adverse effects; D002243:Carbolines / Q000627:therapeutic use; D002998:Clonazepam / Q000627:therapeutic use; D003975:Diazepam / Q000627:therapeutic use; D004597:Electroshock; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D007696:Kindling, Neurologic / Q000502:physiology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D010433:Pentylenetetrazole / Q000009:adverse effects / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control
chemical_list: D000927:Anticonvulsants; D002243:Carbolines; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; C102304:NNC 14-0185; C102305:NNC 14-0189; D011799:Quinazolines; D005442:Flumazenil; D002998:Clonazepam; C062769:abecarnil; D003975:Diazepam; D010433:Pentylenetetrazole; D001640:Bicuculline