New (arylalkyl)azole derivatives showing anticonvulsant effects could have VGSC and/or GABAAR affinity according to molecular modeling studies
Küçük Resim Yok
Tarih
2016
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Elsevier France-Editions Scientifiques Medicales Elsevier
Erişim Hakkı
info:eu-repo/semantics/closedAccess
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-yeethanone 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 gamma-aminobutiric acid (GABA)-mediated response. In order to get insights into the effects of our compounds on VGSCs and A type GABA receptors (GABA(A)Rs) we performed docking studies using homology model of Na+ channel inner pore and GABA(A)R 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. (C) 2016 Elsevier Masson SAS. All rights reserved.
Açıklama
Anahtar Kelimeler
(Arylalkyl)azole, Anticonvulsant, Voltage gated sodium channel, A-type GABA receptor, Molecular docking, X-ray crystallography, Microwave chemistry
Kaynak
European Journal of Medicinal Chemistry
WoS Q Değeri
Q1
Scopus Q Değeri
Q1
Cilt
124
