title: Synthesis and biological evaluation of new GABA-uptake inhibitors derived from proline and from pyrrolidine-2-acetic acid.
abstract: Several synthetic approaches to N-alkylated derivatives of 4-hydroxypyrrolidine-2-carboxylic acid and 4-hydroxypyrrolidine-2-acetic acid are described. The final compounds have been evaluated as potential inhibitors of the GABA transport proteins GAT-1 and GAT-3. The biological assays used were based on bovine material or porcine brain. As compared to the corresponding 4-unsubstituted compounds, the 4-hydroxypyrrolidine-2-carboxylic acid and 4-hydroxypyrrolidine-2-acetic acid derivatives showed a significant decrease in the inhibitory potency at both GAT-1 and GAT-3 with only four compounds having reasonable affinity to GAT-1 (IC(50): 5.1, 6.6 and 9.4 microM) or GAT-3 (IC(50): 19.9 microM), respectively. The biological data of the 4-hydroxypyrrolidine-2-acetic acid derivatives indicates that (2S)-configuration at the C-2 position for potent inhibition of GAT-1 and (4R)-configuration at the C-4 position for potent inhibition of GAT-3 may be crucial.
authors.affiliation: Department für Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Zhao
authors.forename: Cornelia E
authors.initials: CE
authors.lastname: Hoesl
authors.forename: Georg C
authors.initials: GC
authors.lastname: Hoefner
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Wanner
mesh_terms: D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D018756:GABA Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D050485:GABA Plasma Membrane Transport Proteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013552:Swine; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D005680:gamma-Aminobutyric Acid; D011392:Proline; C010983:homoproline