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

    Research output: Contribution to journalArticle

    50 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
    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

    Cite this

    Deniau, Gildas ; Slawin, Alexandra M. Z. ; Lebl, Tomas ; Chorki, Fatima ; Issberner, Jon P. ; van Mourik, Tna ; Heygate, Judith M. ; Lambert, Jeremy J. ; Etherington, Lori-An ; Sillar, Keith T. ; O'Hagan, David. / 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. In: ChemBioChem. 2007 ; Vol. 8, No. 18. pp. 2265-2274.
    @article{9a0d1243ecdd4fd1949544ef0f7bbff9,
    title = "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",
    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).",
    keywords = "density functional calculations, fluorine, GABA, neurotransmitters, NMR spectroscopy, GAMMA-AMINOBUTYRIC-ACID, STEREOSELECTIVE-SYNTHESIS, ASYMMETRIC-SYNTHESIS, AMINO-ALCOHOLS, RECEPTOR, PHARMACOLOGY, ACTIVATION, STABILIZATION, FLUORINATION, ZWITTERIONS",
    author = "Gildas Deniau and Slawin, {Alexandra M. Z.} and Tomas Lebl and Fatima Chorki and Issberner, {Jon P.} and {van Mourik}, Tna and Heygate, {Judith M.} and Lambert, {Jeremy J.} and Lori-An Etherington and Sillar, {Keith T.} and David O'Hagan",
    year = "2007",
    month = "12",
    day = "17",
    doi = "10.1002/cbic.200700371",
    language = "English",
    volume = "8",
    pages = "2265--2274",
    journal = "ChemBioChem",
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    publisher = "Wiley-VCH",
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    Deniau, G, Slawin, AMZ, Lebl, T, Chorki, F, Issberner, JP, van Mourik, T, Heygate, JM, Lambert, JJ, Etherington, L-A, Sillar, KT & O'Hagan, D 2007, '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', ChemBioChem, vol. 8, no. 18, pp. 2265-2274. https://doi.org/10.1002/cbic.200700371

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

    In: ChemBioChem, Vol. 8, No. 18, 17.12.2007, p. 2265-2274.

    Research output: Contribution to journalArticle

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    T1 - Synthesis, conformation and biological evaluation of the enantiomers of 3-fluoro-gamma-aminobutyric acid ((R)- and (S)-3F-GABA)

    T2 - An analogue of the neurotransmitter GABA

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    AU - Slawin, Alexandra M. Z.

    AU - Lebl, Tomas

    AU - Chorki, Fatima

    AU - Issberner, Jon P.

    AU - van Mourik, Tna

    AU - Heygate, Judith M.

    AU - Lambert, Jeremy J.

    AU - Etherington, Lori-An

    AU - Sillar, Keith T.

    AU - O'Hagan, David

    PY - 2007/12/17

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    N2 - 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).

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    KW - neurotransmitters

    KW - NMR spectroscopy

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    KW - STEREOSELECTIVE-SYNTHESIS

    KW - ASYMMETRIC-SYNTHESIS

    KW - AMINO-ALCOHOLS

    KW - RECEPTOR

    KW - PHARMACOLOGY

    KW - ACTIVATION

    KW - STABILIZATION

    KW - FLUORINATION

    KW - ZWITTERIONS

    U2 - 10.1002/cbic.200700371

    DO - 10.1002/cbic.200700371

    M3 - Article

    VL - 8

    SP - 2265

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    JF - ChemBioChem

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