Synthesis and biological evaluation of (R)-N-(diarylmethylthio/sulfinyl)ethyl/propyl-piperidine-3-carboxylic acid hydrochlorides as novel GABA uptake inhibitors |
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Authors: | Zhang Jiange Zhang Pei Liu Xianbo Fang Kai Lin Guoqiang |
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Institution: | Department of Medicinal Chemistry, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China. jgzhang5500@hotmail.com |
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Abstract: | 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 gamma-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 (3)H]-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. |
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