Synthesis, Conformation and Biological Evaluation of the Enantiomers of 3-Fluoro-γ-Aminobutyric Acid ((R)- and (S)-3F-GABA): An Analogue of the Neurotransmitter GABA

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).