Structure activity relationship of selective GABA uptake inhibitors

  • Bioorg Med Chem. 2015 May 15;23(10):2480-8. doi: 10.1016/j.bmc.2015.03.060.
Stine B Vogensen  1 ,  Lars Jørgensen  1 ,  Karsten K Madsen  1 ,  Andreas Jurik  2 ,  Nrupa Borkar  1 ,  Emiliano Rosatelli  3 ,  Birgitte Nielsen  1 ,  Gerhard F Ecker  2 ,  Arne Schousboe  1 ,  Rasmus P Clausen  4
Affiliations
  • 1. University of Copenhagen, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, 2100 Copenhagen, Denmark.
  • 2. University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14, A-1090 Vienna, Austria.
  • 3. University of Perugia, Department of Pharmaceutical Sciences, Via del Liceo 1, Perugia I-06123, Italy.
  • 4. University of Copenhagen, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, 2100 Copenhagen, Denmark. Electronic address: [email protected].
PMID: 25882526 DOI: 10.1016/j.bmc.2015.03.060
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.

Keywords
BGT-1; GABA uptake; Inhibitors; Tiagabine; mGAT2.