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

gamma-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&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 mu M at GAT-3, 21 mu M at GAT-2, >200 mu M at GAT-1, and 140 mu M at BGT-1. This compound will be an important tool for evaluating the role of GAT-3 in neural function.