Özet:
(Arylalkyl)azoles (AAAs) emerged as a novel class of antiepileptic agents with the invention of nafimidone
and denzimol. Several AAA derivatives with potent anticonvulsant activities have been reported so
far, however neurotoxicity was usually an issue. We prepared a set of ester derivatives of 1-(2-naphthyl)-
2-(1H-1,2,4-triazol-1-yl)ethanone oxime and evaluated their anticonvulsant and neurotoxic effects in
mice. Most of our compounds were protective against maximal electroshock (MES)- and/or subcutaneous
metrazol (s.c. MET)-induced seizures whereas none of them showed neurotoxicity. Nafimidone
and denzimol have an activity profile similar to that of phenytoin or carbamazepine, both of which are
known to inhibit voltage-gated sodium channels (VGSCs) as well as to enhance g-aminobutiric acid
(GABA)-mediated response. In order to get insights into the effects of our compounds on VGSCs and Atype
GABA receptors (GABAARs) we performed docking studies using homology model of Naþ channel
inner pore and GABAAR as docking scaffolds. We found that our compounds bind VGSCs in similar ways
as phenytoin, carbamazepine, and lamotrigine. They showed strong affinity to benzodiazepine (BZD)
binding site and their binding interactions were mainly complied with the experimental data and the
reported BZD binding model.
