title: Aminomethyltetrazoles as potential inhibitors of the γ-aminobutyric acid transporters mGAT1-mGAT4: synthesis and biological evaluation.
abstract: 1,5-Disubstituted and 5-monosubstituted aminomethyltetrazole derivatives derived from glycine were synthesized employing a TMSN(3)-modified variant of the Ugi reaction as a key step. All compounds were evaluated regarding their inhibitory potency and subtype selectivity at the four murine GABA transporter subtypes mGAT1-mGAT4. Though none of the 5-monosubstituted tetrazoles turned out to inhibit [(3)H]GABA uptake to a significant extent, the 1,5-disubstituted tetrazole derivatives displayed a distinct activity, especially at the GABA transport proteins mGAT2-mGAT4. Thus, a reasonable potent and selective inhibitor of mGAT3 was found. Additionally, two more compounds were identified as potent inhibitors of mGAT2. This is especially relevant, as up to date only few potent inhibitors of mGAT2 that do not affect mGAT1 are known.
authors.affiliation: Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-University Munich, Butenandtstr. 5-13, D-81377 Munich, Germany.
authors.forename: Eva S
authors.initials: ES
authors.lastname: Schaffert
authors.forename: Georg
authors.initials: G
authors.lastname: Höfner
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Wanner
mesh_terms: D000818:Animals; D002460:Cell Line; D002493:Central Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism*; D058805:GABA Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship; D053719:Tandem Mass Spectrometry; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; D005998:Glycine; D013777:Tetrazoles; C079264:Slc6a11 protein, mouse