Anticonvulsant properties of 1,4-benzodiazepine derivatives in amygdaloid-kindled seizures and their chemical structure-related anticonvulsant action.
The effects of 14 different 1,4-benzodiazepines on amygdaloid-kindled seizures and their chemical structure-related anticonvulsive actions were studied. The prophylactic effects of 1, 4-benzodiazepines on amygdaloid-kindled seizures were also examined. Male Wistar strain rats were used in this study. Rats were anesthetized with pentobarbital sodium (35 mg/kg i.p.) and bipolar electrodes were implanted into the right amygdala. The stimulating parameters were 1 ms pulse duration, 60 Hz frequency and a 1 s duration at an intensity just sufficient to induce afterdischarge (AD). All the 1,4-benzodiazepines depressed both seizure stage and AD duration of amygdaloid-kindled seizures. Of the 1, 4-benzodiazepines, prazepam, flutoprazepam and flurazepam with a long alkyl chain at position 1 were less effective than the drugs having a hydrogen or methyl group at the same position. Nitrazepam, nimetazepam, flunitrazepam and clonazepam which have a nitro group at position 7 showed more potent antiepileptic activity than the drugs with a chloro group. Certain 1,4-benzodiazepines caused inhibition of the development of amygdaloid-kindled seizures. The existence of a hydrogen or methyl group at position 1 and a nitro group at position 7 is important for exhibiting potent anticonvulsant activity in amygdaloid-kindled seizures. Introduction of an oxygen group at position 2 is also necessary for high activity. 1,4-benzodiazepines had not only therapeutic but also prophylactic effects on amygdaloid-kindled seizures.
Fukinaga
M
M
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Ishizawa
K
K
Kamei
C
C
D000679:Amygdala / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D000927:Anticonvulsants / Q000627:therapeutic use*; D001569:Benzodiazepines; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D001569:Benzodiazepines