title: 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.
abstract: We synthesized proline and pyrrolidine-2-alkanoic acid derivatives in their enantiomerically pure form and evaluated them for their affinity to the GABA transport proteins GAT-1 and GAT-3. Among the compounds presented herein, (R)-pyrrolidine-2-acetic acid (R)-4d substituted with a 2-[tris(4-methoxyphenyl)methoxy]ethyl residue at the nitrogen atom showed the highest affinity at GAT-3 (IC(50) = 3.1 microM) comparable with the well-known GAT-3 blocker (S)-SNAP-5114. Compound (R)-4d displayed excellent subtype selectivity for GAT-3 (GAT-3:GAT-1 = 20:1). (S)-2-pyrrolidineacetic acid derivatives (S)-4b provided with a 4,4-diphenylbut-3-en-1-yl moiety and (S)-4c substituted with a 4,4-[di(3-methylthiophen-2-yl)]phenylbut-3-en-1-yl residue at the nitrogen atom exhibited IC(50) values of 0.396 microM and 0.343 microM at the GAT-1 protein, respectively.
authors.affiliation: Department Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Germany.
authors.forename: Günther H
authors.initials: GH
authors.lastname: Fülep
authors.forename: Cornelia E
authors.initials: CE
authors.lastname: Hoesl
authors.forename: Georg
authors.initials: G
authors.lastname: Höfner
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Wanner
mesh_terms: D000473:Alkanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000478:Alkylation; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism*; D058805:GABA Uptake Inhibitors; D008745:Methylation; D015394:Molecular Structure; D011392:Proline / Q000737:chemistry*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry*; D012503:Saponins / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000473:Alkanes; D002264:Carboxylic Acids; D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; D011759:Pyrrolidines; D012503:Saponins; D005680:gamma-Aminobutyric Acid; D011392:Proline; C032519:pyrrolidine