Exploring GABA_A receptor modulation through integrated synthesis, bioactivity, and computational approach of 1,2,4-triazine derivatives

Epilepsy, a prevalent neurological disorder, is often treated with antiepileptic drugs (AEDs), which frequently suffer from toxicity, intolerance, and limited efficacy. Addressing these challenges, our study explores novel 1,2,4-triazine derivatives as potential AEDs. We designed, synthesized, and evaluated the anticonvulsant activity of derivatives HRS1-HRS42 in vivo, notably in the maximal electroshock (MES) and Strychnine-induced convulsion models. Compounds HRS4 and HRS9 demonstrated significant anticonvulsive activity, with HRS9 exhibiting a higher effective dose (ED₅₀ of 28.6 mg/kg) compared to traditional drugs like phenytoin (9.5 mg/kg) and carbamazepine (8.8 mg/kg). Additionally, these compounds displayed antioxidant properties through DPPH and FRAP assays. Compound HRS9 significantly altered neurotransmitter levels, increasing GABA and reducing glutamate in the brain tissue and cortex, which correlates with reduced seizure activity. Acute safety studies confirmed the safety of compound HRS9, with no significant pathological changes observed in histopathological analyses. Molecular interactions were analyzed using Field-based Gaussian 3D-QSAR, highlighting the importance of steric and hydrophobic effects in molecule design. Furthermore, docking studies demonstrated effective binding of compounds to alpha subunit sites within the GABA_A receptor complex, corroborating the biochemical efficacy observed. Molecular dynamics in aqueous medium, and lipid bilayer environment and density functional theory further provided insights into the stability of ligand binding and electronic properties, critical for rational drug design. This comprehensive evaluation not only underscores the potential of 1,2,4-triazine derivatives in advancing the design of new molecules against epilepsy but also sets the stage for subsequent clinical studies to further explore their therapeutic viability.