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 |
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Authors: | Deniau Gildas Slawin Alexandra M Z Lebl Tomas Chorki Fatima Issberner Jon P van Mourik Tanja Heygate Judith M Lambert Jeremy J Etherington Lori-An Sillar Keith T O'Hagan David |
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Affiliation: | School of Chemistry and Centre for Biomolecular Sciences, University of St. Andrews, St. Andrews, Fife, KY16 9ST, Scotland, UK. |
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Abstract: | Gamma-aminobutyric acid or GABA (1) is one of the major inhibitory amino acid neurotransmitters of the central nervous system. This article describes the first synthesis of both the (R)- and (S)- enantiomers 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 GABA(A) receptors; however, they behave quite differently in a whole animal (Xenopus laevis tadpole model). |
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Keywords: | density functional calculations fluorine GABA neurotransmitters NMR spectroscopy |
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