Synthesis and biological evaluation of new derivatives of 2-substituted 4-hydroxybutanamides as GABA uptake inhibitors

Eur J Med Chem. 2011 Jan;46(1):183-90. doi: 10.1016/j.ejmech.2010.11.001. Epub 2010 Nov 4.

Abstract

This study presents the synthesis of novel substituted 4-hydroxybutanamides and their influence on the activity of murine GABA transport proteins GAT1-GAT4. The active compounds, derivatives of N-arylalkyl-2-(4-diphenylmethylpiperazin-1-yl)-4-hydroxybutyramide, are characterized by pIC(50) values in range of 3.92-5.06 and by slight subtype-selectivity. Among them N-4-chlorobenzylamide was the most potent GAT inhibitor (mGAT3), while N-benzylamide was the most active in GAT1-binding assay (pK(i) = 4.96). The results pointed out that benzhydryl and benzylamide moieties are crucial for the activity of this class of compounds as murine GAT inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / chemical synthesis
  • Anticonvulsants / chemistry*
  • Anticonvulsants / pharmacology*
  • Biological Transport / drug effects
  • Butanols / chemical synthesis
  • Butanols / chemistry*
  • Butanols / pharmacology*
  • Drug Evaluation, Preclinical
  • GABA Plasma Membrane Transport Proteins / metabolism
  • GABA Uptake Inhibitors / chemical synthesis
  • GABA Uptake Inhibitors / chemistry*
  • GABA Uptake Inhibitors / pharmacology*
  • Inhibitory Concentration 50
  • Mice
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Anticonvulsants
  • Butanols
  • GABA Plasma Membrane Transport Proteins
  • GABA Uptake Inhibitors
  • gamma-Aminobutyric Acid