title: Design, synthesis and SAR studies of GABA uptake inhibitors derived from 2-substituted pyrrolidine-2-yl-acetic acids.
abstract: In this paper, we disclose the design and synthesis of a series of 2-substituted pyrrolidine-2-yl-acetic acid as core structures and the N-arylalkyl derivatives thereof as potential GABA transport inhibitors. The 2-position in the side chain of pyrrolidine-2-yl-acetic acid derivatives was substituted with alkyl, hydroxy and amino groups to modulate the activity and selectivity to mGAT1 and mGAT4 proteins. SAR studies of the compounds performed for the four mouse GABA transporter proteins (mGAT1-mGAT4) implied significant potencies and subtype selectivities for 2-hydroxy-2-pyrrolidine-2-yl-acetic acid derivatives. The racemate rac-(u)-13c exhibited the highest potency (pIC50 5.67) at and selectivity for mGAT1 in GABA uptake assays. In fact, the potency of rac-(u)-13c at hGAT-1 (pIC50 6.14) was even higher than its potency at mGAT1. These uptake results for rac-(u)-13c are in line with the binding affinities to the aforesaid proteins mGAT1 (pKi 6.99) and hGAT-1 (pKi 7.18) determined by MS Binding Assay based on NO711 as marker quantified by LC-ESI-MS-MS analysis. Interestingly, the 2-hydroxy-2-pyrrolidine-2-yl-acetic acid rac-(u)-13d containing 2-{[tris(4-methoxyphenyl)]methoxy} ethyl group at the nitrogen atom of the pyrrolidine ring showed high potency at mGAT4 and a comparatively better selectivity for this protein (>15 against mGAT3) than the well known mGAT4 uptake inhibitor (S)-SNAP-5114.
authors.affiliation: Department für Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, D-81377 Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Steffan
authors.affiliation: Department für Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, D-81377 Munich, Germany.
authors.forename: Thejavathi
authors.initials: T
authors.lastname: Renukappa-Gutke
authors.affiliation: Department für Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, D-81377 Munich, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Höfner
authors.affiliation: Department für Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, D-81377 Munich, Germany. Electronic address: klaus.wanner@cup.uni-muenchen.de.
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Wanner
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; D011392:Proline; C010983:homoproline
keywords: 2-Substituted pyrrolidine-2-yl-acetic acid; CNS; GABA uptake; N-Acylpyrrolidinium ion; SAR