Synthesis, conformation and biological evaluation of the enantiomers of 3-fluoro-gamma-aminobutyric acid ((R)- and (S)-3F-GABA): An analogue of the neurotransmitter GABA

Gildas Deniau, Alexandra Martha Zoya Slawin, Tomas Lebl, Fatima Chorki, Jon P. Issberner, Tanja Van Mourik, Judith M. Heygate, Jeremy J. Lambert, Lori-An Etherington, Keith Thomas Sillar, David O'Hagan

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61 Citations (Scopus)

Abstract

gamma-Aminobutyric acid or GABA (1) is one of the major inhibitory amino acid neuro transmitters of the central nervous system. This article describes the first synthesis of both the (R)- and (S)- enontiomers of 3-fluoro-GABA (2, 3F-GABA). DFT calculations were carried out in a continuum solvent model (PCM-B3LYP) to estimate the preferred conformations of 3F-GABA in aqueous solution. NMR coupling constants were calculated for each conformer and were then used to simulate the NMR spectra to evaluate the solution conformation of 3F-GABA. A preliminary evaluation of the 3F-GABA enantiomers shows that they act similarly as agonists of cloned GABAA receptors; however, they behave quite differently in a whole animal (Xenopus laevis tadpole model).

Original languageEnglish
Pages (from-to)2265-2274
Number of pages10
JournalChemBioChem
Volume8
DOIs
Publication statusPublished - 17 Dec 2007

Keywords

  • density functional calculations
  • fluorine
  • GABA
  • neurotransmitters
  • NMR spectroscopy
  • GAMMA-AMINOBUTYRIC-ACID
  • STEREOSELECTIVE-SYNTHESIS
  • ASYMMETRIC-SYNTHESIS
  • AMINO-ALCOHOLS
  • RECEPTOR
  • PHARMACOLOGY
  • ACTIVATION
  • STABILIZATION
  • FLUORINATION
  • ZWITTERIONS

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