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Epilepsy and other seizure disorders are not adequately managed with currently available drugs. We recently synthesized a series of dibromophenyl enaminones and demonstrated that AK6 and E249 were equipotent to previous analogs but more efficacious in suppressing neuronal excitation. Here we examined the actions of these lead compounds on  in vitro  and  in vivo  seizure models.  In vitro  seizures were induced in the hippocampal slice chemically (zero Mg 2+  buffer and picrotoxin) and electrically using patterned high frequency stimulation (HFS) of afferents.  In vivo  seizures were induced in rats using the 6 Hz and the maximal electroshock models. AK6 (10 µM) and E249 (10 µM) depressed the amplitude of population spikes recorded in area CA1 of the hippocampus by −50.5±4.3% and −40.1±3.1% respectively, with partial recovery after washout. In the zero Mg 2+  model, AK6 (10 µM) depressed multiple population spiking (mPS) by −59.3±6.9% and spontaneous bursts (SBs) by −65.9±7.2% and in the picrotoxin-model by −43.3±7.2% and −50.0±8.3%, respectively. Likewise, E249 (10 µM) depressed the zero-Mg 2+ -induced mPS by −48.8±9.5% and SBs by −55.8±15.5%, and in the picrotoxin model by −37.1±5.5% and −56.5±11.4%, respectively. They both suppressed post-HFS induced afterdischarges and SBs. AK6 and E249 dose-dependently protected rats in maximal electroshock and 6 Hz models of  in vivo  seizures after 30 min pretreatment. Their level of protection in both models was similar to that obtained with phenytoin Finally, while AK6 had no effect on locomotion in rats, phenytoin significantly decreased locomotion. AK6 and E249, suppressed  in vitro  and  in vivo  seizures to a similar extent. Their  in vivo  activities are comparable with but not superior to phenytoin. The most efficacious, AK6 produced no locomotor suppression while phenytoin did. Thus, AK6 and E249 may be excellent candidates for further investigation as potential agents for the treatment of epilepsy syndromes with possibly less CNS side effects.

Evaluation of Anticonvulsant Actions of Dibromophenyl Enaminones Using In Vitro and In Vivo Seizure Models