Selective mGAT2 (BGT-1) GABA Uptake Inhibitors: Design, Synthesis, and Pharmacological Characterization

β-Amino acids sharing a lipophilic diaromatic side chain were synthesized and characterized pharmacologically on mouse GABA transporter subtypes mGAT1–4. The parent amino acids were also characterized. Compounds 13a, 13b, and 17b displayed more than 6-fold selectivity for mGAT2 over mGAT1. Compound...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2013-03, Vol.56 (5), p.2160-2164
Main Authors: Vogensen, Stine B, Jørgensen, Lars, Madsen, Karsten K, Borkar, Nrupa, Wellendorph, Petrine, Skovgaard-Petersen, Jonas, Schousboe, Arne, White, H. Steve, Krogsgaard-Larsen, Povl, Clausen, Rasmus P
Format: Article
Language:English
Subjects:
Animals
Cells, Cultured
GABA Plasma Membrane Transport Proteins - drug effects
GABA Uptake Inhibitors - chemical synthesis
GABA Uptake Inhibitors - pharmacology
Inhibitory Concentration 50
Isoxazoles - pharmacology
Mice
Neurons - drug effects
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Summary:β-Amino acids sharing a lipophilic diaromatic side chain were synthesized and characterized pharmacologically on mouse GABA transporter subtypes mGAT1–4. The parent amino acids were also characterized. Compounds 13a, 13b, and 17b displayed more than 6-fold selectivity for mGAT2 over mGAT1. Compound 17b displayed anticonvulsive properties inferring a role of mGAT2 in epileptic disorders. These results provide new neuropharmacological tools and a strategy for designing subtype selective GABA transport inhibitors.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm301872x