Design, synthesis and evaluation of substituted triarylnipecotic acid derivatives as GABA uptake inhibitors: Identification of a ligand with moderate affinity and selectivity for the cloned human GABA transporter GAT- 3

Article abstract of DOI:10.1021/jm00041a012

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system. Molecular biology has revealed the presence of four high-affinity GABA transporters in the brain, GAT-1, GAT-2, GAT-3, and BGT-1, the latter transporting both GABA and the osmolyte Betaine. We have shown that known GABA uptake inhibitors such as SK and F 89976-A, CI- 966, and Tiagabine exhibit high affinity and selectivity for GAT-1. In the present paper we describe the design and synthesis of a novel series of triarylnipecotic acid derivatives for evaluation as GABA uptake inhibitors. The design lead for this series of compounds was the nonselective GABA uptake inhibitor EGYT-3886, [(-)-2-phenyl-2-[(dimethylamino)ethoxy]-(1R)-1,7,7- trimethylbicyclo[2.2.1]heptane]. From this series of compounds (S)-1-[2- [tris(4-methoxyphenyl)methoxy]ethyl]-3-piperidinecarboxylic acid, 4(S) was identified as a novel ligand with selectivity for GAT-3. 4(S) displayed an IC₅₀ of 5 μM at GAT-3, 21 μM at GAT-2, >200 μM at GAT-1, and 140 μM at BGT-1. This compound will be an important tool for evaluating the role of GAT-3 in neural function.