2-Substituted 4-hydroxybutanamides as potential inhibitors of γ-aminobutyric acid transporters mGAT1-mGAT4: synthesis and biological evaluation

Bioorg Med Chem. 2013 Sep 1;21(17):5154-67. doi: 10.1016/j.bmc.2013.06.038. Epub 2013 Jun 26.

Abstract

A series of 2-substituted 4-hydroxybutanamide derivatives has been synthesized by the aminolysis of appropriate 2-substituted dihydrofuran-2(3H)-one derivatives with various substituted benzylamines. The final compounds have been evaluated for their capability of inhibiting the GABA transport proteins GAT1-4 stably expressed in HEK-239 cell lines. The pIC50 values determined were in the range 4.21-5.14. Two compounds (16a and 16d), which displayed the most interesting profiles in in vitro tests, have also been subjected to further preliminary behavioral studies, evaluating their antinociceptive activity in hot-plate, writhing, and formalin tests. Their influence on motor coordination has also been assessed.

Keywords: Butanamides; GABA uptake inhibitors; GAT1-4; Motor deficits; Paw licking response; Stretching behavior.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / pharmacology
  • Animals
  • Behavior, Animal / drug effects
  • GABA Plasma Membrane Transport Proteins / chemistry*
  • GABA Plasma Membrane Transport Proteins / genetics
  • GABA Plasma Membrane Transport Proteins / metabolism
  • GABA Uptake Inhibitors / chemical synthesis
  • GABA Uptake Inhibitors / chemistry*
  • GABA Uptake Inhibitors / pharmacology
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Protein Binding
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism

Substances

  • Amides
  • GABA Plasma Membrane Transport Proteins
  • GABA Uptake Inhibitors
  • Protein Isoforms