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. Epub 2015 Mar 30.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemical synthesis
  • Amino Acids / chemistry*
  • Animals
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / chemistry
  • GABA Agonists / chemistry
  • GABA Plasma Membrane Transport Proteins / chemistry*
  • GABA Uptake Inhibitors / chemical synthesis
  • GABA Uptake Inhibitors / chemistry*
  • HEK293 Cells
  • Humans
  • Ligands
  • Mice
  • Molecular Docking Simulation
  • Molecular Structure
  • Nipecotic Acids / chemistry
  • Protein Isoforms / chemistry
  • Structure-Activity Relationship
  • Tiagabine

Substances

  • Amino Acids
  • Carrier Proteins
  • GABA Agonists
  • GABA Plasma Membrane Transport Proteins
  • GABA Uptake Inhibitors
  • Ligands
  • Nipecotic Acids
  • Protein Isoforms
  • betaine plasma membrane transport proteins
  • Tiagabine