piperidines and nipecotic-acid

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.

Topics: Animals; Anticonvulsants; Carboxylic Acids; Chemistry, Pharmaceutical; Drug Design; GABA Antagonists; GABA Plasma Membrane Transport Proteins; gamma-Aminobutyric Acid; Imidazoles; Inhibitory Concentration 50; Mice; Models, Chemical; Nipecotic Acids; Piperidines; Structure-Activity Relationship; Temperature; Tiagabine

The selectivity of new derivatives of the gamma-aminobutyric acid (GABA)-uptake inhibitor, tiagabine was characterized at the four cloned mouse GABA transporters (mGAT1 through mGAT4) by measuring [3H]-GABA uptake into stably transfected baby hamster kidney cells. While tiagabine is a highly selective inhibitor of mGAT1 (Ki = 0.11 +/- 0.02 microM), these derivatives exhibited low potencies at mGAT1 but differential activities at mGAT2, mGAT3 and mGAT4. In particular, 1-(3-(9H-carbazol-9-yl)-1-propyl)-4-(2-methoxyphenyl)-4-piperidino l (NNC 05-2090) was a potent inhibitor of mGAT2 (Ki = 1.4 +/- 0.3 microM) showing at least 10 fold selectivity over mGAT1, mGAT3 and mGAT4. NNC 05-2090 is the first subtype selective inhibitor of mGAT2 and may represent a novel useful tool for investigating the physiological roles of GAT2 in the brain and periphery.

Topics: Animals; Carrier Proteins; Cell Line; Cricetinae; GABA Plasma Membrane Transport Proteins; gamma-Aminobutyric Acid; Membrane Proteins; Membrane Transport Proteins; Mice; Neurotransmitter Uptake Inhibitors; Nipecotic Acids; Organic Anion Transporters; Piperidines; Proline; Tiagabine

Although considered selective for its natural substrate, 4-aminobutyrate, gab permease was inhibited by 1,2,3,6-tetrahydro-3-pyridinecarboxylate and 1,2,3,6-tetrahydro-4-pyridinecarboxylate. The former is a transported substrate, since its preloading into metabolically poisoned cells stimulated transient accumulation of 4-aminobutyrate via counterflow.

Topics: Biological Transport; Escherichia coli; Escherichia coli Proteins; GABA Plasma Membrane Transport Proteins; gamma-Aminobutyric Acid; Genes, Bacterial; Membrane Transport Modulators; Membrane Transport Proteins; Nicotinic Acids; Nipecotic Acids; Organic Anion Transporters; Piperidines; Proline; Substrate Specificity

Topics: Animals; Antibodies, Helminth; Cross Reactions; Diethylcarbamazine; Enzyme-Linked Immunosorbent Assay; Haptens; Microfilariae; Nipecotic Acids; Piperazines; Piperidines; Proline; Wuchereria bancrofti