Löscher W, Schneider H, Kehr W
Eur J Pharmacol. 1985 Aug 27;114(3):261-6. doi: 10.1016/0014-2999(85)90368-1.
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.
对三种β-咔啉类苯二氮䓬（BZ）受体配体进行了研究，它们分别是BZ受体激动剂ZK 93 423、部分激动剂ZK 91 296和拮抗剂ZK 93 426，研究对象为患有不同癫痫发作类型的癫痫易感蒙古沙鼠。这些研究中纳入了地西泮和氯硝西泮作为对照。对沙鼠进行的体内结合研究表明，所有化合物都能有效地将[3H]氯美扎酮从大脑小脑和前脑的结合位点上置换下来。除ZK 93 426外，所有药物都能剂量依赖性地保护沙鼠免受气爆刺激诱发的轻微（肌阵挛性）和严重（强直阵挛性）癫痫发作。对于ZK 93 423、ZK 91 296、地西泮和氯硝西泮，发现抗惊厥ED50与[3H]氯美扎酮结合置换的ED50之间存在高度显著的相关性。受体占有率的计算表明，β-咔啉类和苯二氮䓬类在低占有率（前脑为8-15%）时对沙鼠具有抗惊厥作用。即使在几乎完全受体占有率的情况下，BZ受体拮抗剂ZK 93 426对癫痫发作行为也没有任何影响，但能拮抗ZK 91 296的抗惊厥作用。与地西泮不同，即使在受体占有率达到90%时，ZK 91 296也没有任何镇静副作用。数据表明，抗惊厥β-咔啉类作为一种新型抗惊厥药物值得关注。
