Anticonvulsant Properties of 1,4-Benzodiazepine Derivatives in Amygdaloid-Kindled Seizures and Their Chemical Structure-Related Anticonvulsant Action

Abstract

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.

Privileged Structures - Dream or Reality: Preferential Organization of Azanaphthalene Scaffold

“…Diazepam [67,83] Lorazepam [84] Nimetazepam [85] Midazolam [84] Cyclizine [67,86] Buclizine [87] Hydroxyzine [88] Cetirizine [89] N H…”

Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model

“…To provide a validated positive control, in the present study we conducted a parallel series of experiments with clonazepam, which is well recognized to protect against amygdala kindled seizures (Ashton and Wauquier, 1979; Albertson et al, 1980; Löscher et al, 1986; Tietz et al, 1989; Fukinaga et al, 1998). As expected, pretreatment with clonazepam caused a dose-dependent inhibition of seizure stage and duration that was similar to that produced by ganaxolone, except that clonazepam was substantially more potent on a molar basis.…”

“…Since ganaxolone is under clinical development, we sought to characterize its activity in the amygdala kindling model in mice. For comparison, we conducted parallel experiments with clonazepam, which has previously been shown to be highly effective against amygdala kindled seizures (Ashton and Wauquier, 1979; Albertson et al, 1980; Löscher et al, 1986; Tietz et al, 1989; Fukinaga et al, 1998). Our results indicate that, in fully kindled mice, ganaxolone produces a marked suppression of stimulation-evoked behavioral seizures and electrographic seizure activity, supporting the potential utility of ganaxolone to treat complex partial seizures.…”

In Silico Design of Potential 1, 5-Benzothiazepine Derivatives as an Anti - Convulsant Agent by Molecular Docking Studies

“…In turn, this knowledge is aimed at designing new active molecules that can be successfully used as drugs. Because simulation accuracy is limited to the precision of the constructed models, when it is possible, computational simulations have to be compared with experimental results to confirm model accuracy and to modify them if necessary, in order to obtain better representations of the system [4][5][6].…”