Synthesis and biological evaluation of (R)-N-(diarylmethylthio/sulfinyl)ethyl/propyl-piperidine-3-carboxylic acid hydrochlorides as novel GABA uptake inhibitors

A series of new (R)-1-(2-diarylmethylthio/sulfinyl)ethyl-piperidine-3-carboxylic acid hydrochlorides 5a–d/6a–d and (R)-1-(3-diarylmethylthio)propyl-piperidine-3-carboxylic acid hydrochlorides 5′a–d were synthesized and evaluated as γ-aminobutyric acid uptake inhibitors through cultured cell lines expressing mouse GAT1. Biological screening results demonstrated that the compounds 6a–d with diarylmethylsulfinyl ethyl side chain show more potent GAT1 inhibitory activities than 5a–d/5′a–d with diarylmethylthio ethyl/propyl moieties. Some of them, such as 6a, exhibited excellent inhibitions of [3H]-GABA uptake in cultured cells, which is 496-fold higher than (R)-nipecotic acid and 11.5 times less than tiagabine. The synthesis and structure–activity relationships are discussed.