title: Potential role of selected antiepileptics used in neuropathic pain as human GABA transporter isoform 1 (GAT1) inhibitors-Molecular docking and pharmacodynamic studies.
abstract: 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.
authors.affiliation: Department of Organic Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 2 dr. A. Jurasza St., 85-094 Bydgoszcz, Poland.
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Fijałkowski
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Cracow, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Sałat
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Cracow, Poland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Podkowa
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Cracow, Poland.
authors.forename: Paula
authors.initials: P
authors.lastname: Zaręba
authors.affiliation: Department of Organic Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 2 dr. A. Jurasza St., 85-094 Bydgoszcz, Poland. Electronic address: alicja@cm.umk.pl.
authors.forename: Alicja
authors.initials: A
authors.lastname: Nowaczyk
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D050485:GABA Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation / Q000379:methods*; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism*; D009557:Nipecotic Acids / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D011485:Protein Binding / Q000502:physiology; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D000078308:Tiagabine
chemical_list: D000927:Anticonvulsants; D050485:GABA Plasma Membrane Transport Proteins; D009557:Nipecotic Acids; D020033:Protein Isoforms; C493413:SLC6A1 protein, human; D000078308:Tiagabine
keywords: Analgesic activity; Antiepileptic drugs; GABA; GHB; Gabapentin (PubChem CID: 6453919); Lamotrigine (PubChem CID: 3878); Molecular docking; Pregabalin (PubChem CID: 5486971); Progabide (PubChem CID: 5361323); R-tiagabine (PubChem CID: 60648); S-tiagabine (PubChem CID: 10452119); Valproic (PubChem CID: 3121); Valpromide (PubChem CID: 71113); Vigabatrin (PubChem CID: 5665); Zonisamide (PubChem CID: 5734); hGAT1