New (arylalkyl)azole derivatives showing anticonvulsant effects could have VGSC and/or GABAAR affinity according to molecular modeling studies.
(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 γ-aminobutiric acid (GABA)-mediated response. In order to get insights into the effects of our compounds on VGSCs and A-type GABA receptors (GABAARs) we performed docking studies using homology model of Na+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.
Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100, Ankara, Turkey.
Suat
S
Sari
İnönü University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 44280, Malatya, Turkey. Electronic address: arzu.karakurt@inonu.edu.tr.
Arzu
A
Karakurt
İnönü University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 44280, Malatya, Turkey.
Harun
H
Uslu
Hacettepe University, Faculty of Engineering, Department of Physics Engineering, 06532, Ankara, Turkey.
F Betül
FB
Kaynak
Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100, Ankara, Turkey.
Ünsal
Ü
Çalış
Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100, Ankara, Turkey.
Sevim
S
Dalkara
D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D001393:Azoles / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D016062:Porosity; D011485:Protein Binding; D011487:Protein Conformation; D011963:Receptors, GABA-A / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy
D000927:Anticonvulsants; D001393:Azoles; D015220:Calcium Channels; D011963:Receptors, GABA-A
(Arylalkyl)azole; A-type GABA receptor; Anticonvulsant; Microwave chemistry; Molecular docking; Voltage gated sodium channel; X-ray crystallography