Probing the Mode of Neurotransmitter Binding to GABA Receptors Using Selectively Fluorinated GABA Analogues

Stereoselective fluorination is a useful technique for controlling the conformations of organic molecules. This concept has been exploited to create conformationally biased analogues of the neurotransmitter gamma-aminobutyric acid (GABA). Mono- and di-fluorinated GABA analogues are found to adopt different conformations, due to subtle stereoelectronic effects associated with the C-F bond. These conformationally biased GABA analogues exhibit different shape-dependent selectivity patterns towards GABA_A, GABA_B, and GABA_C receptors, providing valuable information on the binding modes of the natural ligand at these medicinally important targets.