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.