Structure Activity Relationship of selective GABA uptake inhibitors
- Author(s)
- Stine B. Vogensen, Jørgensen, Lars, Karsten K. Madsen, Andreas Jurik, Nrupa Borkar, Emiliano Rosatelli, Brigitte Nielsen, Gerhard Ecker, Arne Schousboe, Rasmus Praetorius Clausen
- 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.
- Organisation(s)
- External organisation(s)
- University of Copenhagen, Università degli Studi di Perugia
- Journal
- Bioorganic & Medicinal Chemistry
- Volume
- 23
- Pages
- 2480-2488
- No. of pages
- 9
- ISSN
- 0968-0896
- DOI
- https://doi.org/10.1016/j.bmc.2015.03.060
- Publication date
- 05-2015
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301207 Pharmaceutical chemistry
- Keywords
- ASJC Scopus subject areas
- Drug Discovery, Molecular Medicine, Molecular Biology, Biochemistry, Clinical Biochemistry, Pharmaceutical Science, Organic Chemistry
- Portal url
- https://ucris.univie.ac.at/portal/en/publications/structure-activity-relationship-of-selective-gaba-uptake-inhibitors(fed0baf0-2e97-4ea7-9693-dc90ab6521fd).html