3-Fluoro-GABA Enantiomers: Exploring the Conformation of GABA Binding to GABA_A Receptors and GABA Aminotransferase

Abstract

The neurotransmitter GABA is the main inhibitory neurotransmitter of the CNS. It is estimated that 20–50% of all neuronal synapses are GABAergic. Distinct types of GABA receptor have been identified (GABA_A, GABA_B and GABA_AOr [GABA_C]). The GABA_A and GABA_AOr variant found in the retina receptors (informally termed GABA_C) are physiologically related in that they are both ligand (GABA)-gated chloride ion channels. The GABA_B receptor mediates its response by modulating Ca²⁺ and K⁺ ion channels, which then trigger coupled G-proteins. These receptors have not succumbed to x-ray structural analysis at a suitable resolution to determine the nature of GABA binding. However, knowledge of how GABA binds is important for the design of novel agonists and antagonists, and the development of neuropharmaceutical agents. Comparison of the relative agonistic efficacy of the (R)- and (S)-enantiomers of 3-fluoro-GABA has been used as a method to probe the binding conformation of the neurotransmitter binding to target proteins. The analysis relies on the stereoelectronic influence of the C–F bond interacting with the ammonium group of GABA, an electrostatic interaction that favors solution conformers where the substituents come close (gauche rather than anti). This article describes how comparative analysis of these enantiomers has been used to assess the conformation of GABA binding to GABA_A and the GABA-metabolizing enzyme, GABA transaminase.

Acknowledgements

The author thanks Gildas Deniau (St Andrews University) for his contribution to the 3F-GABA project. He also thanks Keith Sillar (University of St Andrews), Jerry Lambert (University of Dundee, UK) and their colleagues for carrying out GABA_A receptor assays, and Richard Silverman (Northwestern University, IL, USA) and his colleagues are greatfully acknowledged for their collaboration on GABA transaminase.

Financial & competing interests disclosure

David O‘Hagan is grateful to the European Research Council for an Advanced Investigator Award. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

David O‘Hagan is grateful to the European Research Council for an Advanced Investigator Award. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.