Evaluation of different beta-carbolines in Mongolian gerbils with reflex epilepsy.
Three benzodiazepine (BZ) receptor ligands of the beta-carboline group, namely the BZ receptor agonist ZK 93 423, the partial agonist ZK 91 296, and the antagonist ZK 93 426, were studied in epilepsy-prone Mongolian gerbils with different seizure types. Diazepam and clonazepam were included in these studies for comparison. In vivo binding studies in gerbils showed that all compounds were potent in displacing [3H]lormetazepam from binding sites in cerebellum and forebrain. Except for ZK 93 426, all drugs proved capable of dose dependently protecting gerbils from minor (myoclonic) and major (tonic-clonic) seizures induced by air blast stimulation. For ZK 93 423, ZK 91 296, diazepam and clonazepam, a highly significant correlation was found between anticonvulsant ED50S and ED50S for displacement of [3H]lormetazepam binding. Calculation of receptor occupancy revealed that beta-carbolines and benzodiazepines displayed anticonvulsant effects in gerbils at low occupancy (8-15% in forebrain). Even at almost total receptor occupancy, the BZ receptor antagonist ZK 93 426 was without any effect on seizure behaviour but antagonized the anticonvulsant effect of ZK 91 296. In contrast to diazepam, ZK 91 296 was devoid of any sedative side-effects even at 90% receptor occupancy. The data suggest that anticonvulsant beta-carbolines deserve interest as a new type of anticonvulsant drug.
D000818:Animals; D000927:Anticonvulsants; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000378:metabolism; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002243:Carbolines / Q000378:metabolism / Q000494:pharmacology*; D002531:Cerebellum / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005849:Gerbillinae; D008297:Male; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism
D000927:Anticonvulsants; D002243:Carbolines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C038933:ZK 91296; C042569:ZK 93423; C042568:ZK 93426