Abstract
We synthesized proline and pyrrolidine-2-alkanoic acid derivatives in their enantiomerically pure form and evaluated them for their affinity to the GABA transport proteins GAT-1 and GAT-3. Among the compounds presented herein, ( R)-pyrrolidine-2-acetic acid ( R)- 4d substituted with a 2-[tris(4-methoxyphenyl)methoxy]ethyl residue at the nitrogen atom showed the highest affinity at GAT-3 (IC 50 = 3.1 μM) comparable with the well-known GAT-3 blocker ( S)-SNAP-5114. Compound ( R)- 4d displayed excellent subtype selectivity for GAT-3 (GAT-3:GAT-1 = 20:1). ( S)-2-pyrrolidineacetic acid derivatives ( S)- 4b provided with a 4,4-diphenylbut-3-en-1-yl moiety and ( S)- 4c substituted with a 4,4-[di(3-methylthiophen-2-yl)]phenylbut-3-en-1-yl residue at the nitrogen atom exhibited IC 50 values of 0.396 μM and 0.343 μM at the GAT-1 protein, respectively.
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