Novel derivatives of phthalimide with potent anticonvulsant activity in PTZ and MES seizure models

Objective(s): Phthalimide-based derivatives have anticonvulsant activity like as phenytoin by inhibition of sodium channel. In our previously research we mentioned about some phthalimide derivatives as potent anticonvulsant agents. Materials and Methods: Fourteen analogs of ۲-substituted phthalimide pharmacophore were synthesized and then were evaluated for the anticonvulsant activities in pentylenetetrazole-induced seizures (PTZ) and maximal electroshock seizure (MES) models. Results: The in vivo screening results showed that all the analogs have the ability to protect against the maximal electroshock and PTZ. The compounds ۳ and ۹ elevated clonic seizure thresholds at ۳۰ min which were more active than the standard medicine phenytoin. Compounds ۳, ۶, ۷, ۱۱, ۱۳ and ۱۴ with ۱۰۰% protection were the most potent ones in tonic seizure. The most potent compound in the both PTZ and MES models was compound ۳. Using a model of the open pore of sodium channel, all of the compounds were docked. Results of docking showed that the ligands interacted mainly with residues II-S۶ of NaV۱.۲ by making hydrogen bonds and have additional hydrophobic interactions with other domains in the channel's inner pore. Conclusion: Some of these compounds are more potent than phenytoin simultaneously in the clonic and tonic seizures.

کلیدواژه ها:

Anticonvulsant ، Docking ، MES seizure ، Phthalimide ، PTZ seizure ، Sodium channel