New Highly Potent GABA Uptake Inhibitors Selective for GAT-1 and GAT-3 Derived from (R)-and (S)-Proline and Homologous Pyrrolidine-2-alkanoic Acids.-Enantiomerically pure N-substituted proline and pyrolidinealkanoic acid derivatives are synthesized and evaluated for their affinity at the GABA transport proteins GAT-1 and GAT-3 with a special emphasis on enantioselectivity of binding and subtype specificity. Among the N-substituted derivatives, pyrrolidines (VII) exhibit the highest affinity to the GAT-1 protein, whereas pyrrolidine (IX) displays excellent inhibitory activity at GAT-3 with a high subtype selectivity with regard to GAT-1. -(FUELEP, G. H.; HOESL, C. E.; HOEFNER, G.; WANNER*, K. T.; Eur.
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Azetidine Derivatives as Novel γ-Aminobutyric Acid Uptake Inhibitors: Synthesis, Biological Evaluation, and Structure-Activity Relationship. -Azetidines, e.g. (I)-(III), are synthesized as structural analogues of four known GABA-uptake inhibitors. Their activities strongly depend on both the position of the carboxylic acid moiety and the nature of the lipophilic groups. The highest affinity at GAT-1 is observed for azetidinylacetic acid derivative (I) with a selectivity of 48:1 for GAT-1 over GAT-3. Azetidinecarboxylic acid derivative (II) is the most potent inhibitor of GAT-3 with IC50 of 15.3 μM and a selectivity greater than 7:1 for GAT-3 over GAT-1. Derivative (III) reveals moderate potency at and subtype selectivity for GAT-3. -(FAUST, M. R.; HOEFNER, G.; PABEL, J.; WANNER*, K. T.; Eur.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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