Potential role of selected antiepileptics used in neuropathic pain as human GABA transporter isoform 1 (GAT1) inhibitors—Molecular docking and pharmacodynamic studies

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• 作者：Łukasz Fijałkowski^a ; Kinga Sałat^b ; Adrian Podkowa^b ; Paula Zaręba^c ; Alicja Nowaczyk^a ; ^{alicja@cm.umk.pl}
• 关键词：Gabapentin (PubChem CID ; 6453919) ; R-tiagabine (PubChem CID ; 60648) ; S-tiagabine (PubChem CID ; 10452119) ; Lamotrigine (PubChem CID ; 3878) ; Pregabalin (PubChem CID ; 5486971) ; Progabide (PubChem CID ; 5361323) ; Vigabatrin (PubChem CID ; 5665) ; Valproic (PubChem CID ; 3121) ; Valpromide (PubChem CID ; 71113) ; Zonisamide (PubChem CID ; 5734)
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：96
• 期：Complete
• 页码：362-372
• 全文大小：938 K
• 卷排序：96

文摘

The chemical interaction of nine antiepileptic drugs (tiagabine, gabapentin, pregabalin, lamotrigine, zonisamide, valproic acid, valpromide, vigabatrin, progabide) and two endogenous metabolites (4-aminobutanoic acid, 4-hydroxybutanoic acid) with a model of human GABA transporter 1 (hGAT1) is described using the molecular docking method. To establish the role of hGAT1 in chronic pain, tiagabine, a selective hGAT1 inhibitor, was assessed in the in vivo experiments for its antiallodynic properties in two mouse models of neuropathic pain. Docking analyses performed in this study provided the complex binding energies, specific hydrogen bond components, and hydrogen bond properties such as energies, distances and angles. The data of the docking studies strongly support the assumption that the antiepileptic and analgesic actions of the studied drugs can be at least in part related to the strength of their chemical interactions with hGAT1. In vivo experiments with tiagabine confirmed the involvement of hGAT1 in the regulation of the mechanical nociceptive threshold in neuropathic pain.