title: 2-Substituted 4-hydroxybutanamides as potential inhibitors of γ-aminobutyric acid transporters mGAT1-mGAT4: synthesis and biological evaluation.
abstract: A series of 2-substituted 4-hydroxybutanamide derivatives has been synthesized by the aminolysis of appropriate 2-substituted dihydrofuran-2(3H)-one derivatives with various substituted benzylamines. The final compounds have been evaluated for their capability of inhibiting the GABA transport proteins GAT1-4 stably expressed in HEK-239 cell lines. The pIC50 values determined were in the range 4.21-5.14. Two compounds (16a and 16d), which displayed the most interesting profiles in in vitro tests, have also been subjected to further preliminary behavioral studies, evaluating their antinociceptive activity in hot-plate, writhing, and formalin tests. Their influence on motor coordination has also been assessed.
authors.affiliation: Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Paula
authors.initials: P
authors.lastname: Kowalczyk
authors.forename: Kinga
authors.initials: K
authors.lastname: Sałat
authors.forename: Georg C
authors.initials: GC
authors.lastname: Höfner
authors.forename: Natalia
authors.initials: N
authors.lastname: Guzior
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Wanner
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kulig
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D050485:GABA Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D058805:GABA Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000577:Amides; D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; D020033:Protein Isoforms
keywords: Butanamides; GABA uptake inhibitors; GAT1-4; Motor deficits; Paw licking response; Stretching behavior