title: Structure activity relationship of selective GABA uptake inhibitors.
abstract: A series of β-amino acids with lipophilic diaromatic side chain was synthesized and characterized pharmacologically on mouse γ-amino butyric acid (GABA) transporter subtypes mGAT1-4 in order to investigate structure activity relationships (SAR) for mGAT2 (corresponding to hBGT-1). Variation in the lipophilic diaromatic side chain was probed to understand the role of the side chain for activity. This yielded several selective compounds of which the best (1R,2S)-5a was more than 10 fold selective towards other subtypes, although potency was moderate. A docking study was performed to investigate possible binding modes of the compounds in mGAT2 suggesting a binding mode similar to that proposed for Tiagabine in hGAT1. Specific interactions between the transporter and the amino acid part of the ligands may account for a reverted preference towards mGAT2 over mGAT1.
authors.affiliation: University of Copenhagen, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, 2100 Copenhagen, Denmark.
authors.forename: Stine B
authors.initials: SB
authors.lastname: Vogensen
authors.affiliation: University of Copenhagen, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, 2100 Copenhagen, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Jørgensen
authors.affiliation: University of Copenhagen, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, 2100 Copenhagen, Denmark.
authors.forename: Karsten K
authors.initials: KK
authors.lastname: Madsen
authors.affiliation: University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Jurik
authors.affiliation: University of Copenhagen, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, 2100 Copenhagen, Denmark.
authors.forename: Nrupa
authors.initials: N
authors.lastname: Borkar
authors.affiliation: University of Perugia, Department of Pharmaceutical Sciences, Via del Liceo 1, Perugia I-06123, Italy.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Rosatelli
authors.affiliation: University of Copenhagen, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, 2100 Copenhagen, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.affiliation: University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Ecker
authors.affiliation: University of Copenhagen, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, 2100 Copenhagen, Denmark.
authors.forename: Arne
authors.initials: A
authors.lastname: Schousboe
authors.affiliation: University of Copenhagen, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, 2100 Copenhagen, Denmark. Electronic address: rac@sund.ku.dk.
authors.forename: Rasmus P
authors.initials: RP
authors.lastname: Clausen
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018755:GABA Agonists / Q000737:chemistry; D050485:GABA Plasma Membrane Transport Proteins / Q000737:chemistry*; D058805:GABA Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009557:Nipecotic Acids / Q000737:chemistry; D020033:Protein Isoforms / Q000737:chemistry; D013329:Structure-Activity Relationship; D000078308:Tiagabine
chemical_list: D000596:Amino Acids; D002352:Carrier Proteins; D018755:GABA Agonists; D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; D008024:Ligands; D009557:Nipecotic Acids; D020033:Protein Isoforms; C072207:betaine plasma membrane transport proteins; D000078308:Tiagabine
keywords: BGT-1; GABA uptake; Inhibitors; Tiagabine; mGAT2