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 M. Z. Slawin, Tomas Lebl, Fatima Chorki, Jon P. Issberner, Tna van Mourik, Judith M. Heygate, Jeremy J. Lambert, Lori-An Etherington, Keith T. Sillar, David O'Hagan

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    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
    Issue number18
    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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