Selective mGAT2 (BGT-1) GABA uptake inhibitors: design, synthesis, and pharmacological characterization

Stine B Vogensen; Lars Jørgensen; Karsten K Madsen; Nrupa Borkar; Petrine Wellendorph; Jonas Skovgaard-Petersen; Arne Schousboe; H Steve White; Povl Krogsgaard-Larsen; Rasmus P Clausen

doi:10.1021/jm301872x

Selective mGAT2 (BGT-1) GABA uptake inhibitors: design, synthesis, and pharmacological characterization

J Med Chem. 2013 Mar 14;56(5):2160-4. doi: 10.1021/jm301872x. Epub 2013 Feb 27.

Authors

Stine B Vogensen¹, Lars Jørgensen, Karsten K Madsen, Nrupa Borkar, Petrine Wellendorph, Jonas Skovgaard-Petersen, Arne Schousboe, H Steve White, Povl Krogsgaard-Larsen, Rasmus P Clausen

Affiliation

¹ Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.

PMID: 23398473
DOI: 10.1021/jm301872x

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

EF1502
GABA Plasma Membrane Transport Proteins
GABA Uptake Inhibitors
Isoxazoles
Slc6a12 protein, mouse