New highly potent GABA uptake inhibitors selective for GAT-1 and GAT-3 derived from (R)- and (S)-proline and homologous pyrrolidine-2-alkanoic acids

Eur J Med Chem. 2006 Jul;41(7):809-24. doi: 10.1016/j.ejmech.2006.01.019.

Abstract

We synthesized proline and pyrrolidine-2-alkanoic acid derivatives in their enantiomerically pure form and evaluated them for their affinity to the GABA transport proteins GAT-1 and GAT-3. Among the compounds presented herein, (R)-pyrrolidine-2-acetic acid (R)-4d substituted with a 2-[tris(4-methoxyphenyl)methoxy]ethyl residue at the nitrogen atom showed the highest affinity at GAT-3 (IC(50) = 3.1 microM) comparable with the well-known GAT-3 blocker (S)-SNAP-5114. Compound (R)-4d displayed excellent subtype selectivity for GAT-3 (GAT-3:GAT-1 = 20:1). (S)-2-pyrrolidineacetic acid derivatives (S)-4b provided with a 4,4-diphenylbut-3-en-1-yl moiety and (S)-4c substituted with a 4,4-[di(3-methylthiophen-2-yl)]phenylbut-3-en-1-yl residue at the nitrogen atom exhibited IC(50) values of 0.396 microM and 0.343 microM at the GAT-1 protein, respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkanes / chemical synthesis
  • Alkanes / chemistry*
  • Alkanes / pharmacology*
  • Alkylation
  • Carboxylic Acids / chemical synthesis
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology
  • GABA Plasma Membrane Transport Proteins / metabolism*
  • GABA Uptake Inhibitors*
  • Methylation
  • Molecular Structure
  • Proline / chemistry*
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry*
  • Saponins / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Alkanes
  • Carboxylic Acids
  • GABA Plasma Membrane Transport Proteins
  • GABA Uptake Inhibitors
  • Pyrrolidines
  • Saponins
  • gamma-Aminobutyric Acid
  • Proline
  • pyrrolidine