title: Synthesis and biological evaluation of (R)-N-(diarylmethylthio/sulfinyl)ethyl/propyl-piperidine-3-carboxylic acid hydrochlorides as novel GABA uptake inhibitors.
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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China. jgzhang5500@hotmail.com <jgzhang5500@hotmail.com>
authors.forename: Jiange
authors.initials: J
authors.lastname: Zhang
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
authors.forename: Xianbo
authors.initials: X
authors.lastname: Liu
authors.forename: Kai
authors.initials: K
authors.lastname: Fang
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Lin
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D018756:GABA Antagonists / Q000138:chemical synthesis* / Q000737:chemistry; D050485:GABA Plasma Membrane Transport Proteins / Q000737:chemistry / Q000502:physiology*; D007093:Imidazoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D009557:Nipecotic Acids / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013696:Temperature; D000078308:Tiagabine; D005680:gamma-Aminobutyric Acid / Q000493:pharmacokinetics*
chemical_list: D000927:Anticonvulsants; D002264:Carboxylic Acids; D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D007093:Imidazoles; D009557:Nipecotic Acids; D010880:Piperidines; C030278:nipecotic acid; D005680:gamma-Aminobutyric Acid; D000078308:Tiagabine