Efficacy and pharmacokinetics evaluation of 4-(2-chloro-4-fluorobenzyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H)-one (GM-90432) as an anti-seizure agent.
Epilepsy is a common chronic neurological disease characterized by recurrent epileptic seizures. A seizure is an uncontrolled electrical activity in the brain that can cause different levels of behavior, emotion, and consciousness. One-third of patients fail to receive sufficient seizure control, even though more than fifty FDA-approved anti-seizure drugs (ASDs) are available. In this study, we attempted small molecule screening to identify potential therapeutic agents for the treatment of seizures using seizure-induced animal models. Through behavioral phenotype-based screening, 4-(2-chloro-4-fluorobenzyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H)-one (GM-90432) was identified as a prototype. GM-90432 treatment effectively decreased seizure-like behaviors in zebrafish and mice with chemically induced seizures. These results were consistent with decreased neuronal activity through immunohistochemistry for pERK in zebrafish larvae. Additionally, electroencephalogram (EEG) analysis revealed that GM-90432 decreases seizure-specific EEG events in adult zebrafish. Moreover, we revealed the preferential binding of GM-90432 to voltage-gated Na+ channels using a whole-cell patch clamp technique. Through pharmacokinetic analysis, GM-90432 effectively penetrated the blood-brain barrier and was distributed into the brain. Taken together, we suggest that GM-90432 has the potential to be developed into a new ASD candidate.
['Hwang|Kyu-Seok|KS|', 'Kan|Hyemin|H|', 'Kim|Seong Soon|SS|', 'Chae|Jin Sil|JS|', 'Yang|Jung Yoon|JY|', 'Shin|Dae-Seop|DS|', 'Ahn|Se Hwan|SH|', 'Ahn|Jin Hee|JH|', 'Cho|Jin-Hwa|JH|', 'Jang|Il-Sung|IS|', 'Shin|Junnyeong|J|', 'Joo|Jaeyoung|J|', 'Kim|Cheol-Hee|CH|', 'Bae|Myung Ae|MA|']
D000818:Animals D000927:Anticonvulsants D001522:Behavior, Animal D001812:Blood-Brain Barrier D004569:Electroencephalography D007150:Immunohistochemistry D007814:Larva D020935:MAP Kinase Signaling System D008297:Male D008403:Mass Screening D051379:Mice D008813:Mice, Inbred ICR D010069:Oxadiazoles D018408:Patch-Clamp Techniques D012640:Seizures D054852:Small Molecule Libraries D015222:Sodium Channels D015027:Zebrafish
Pharmacokinetics Anti-seizure drug Zebrafish Electroencephalogram Electrophysiology