title: Novel parent structures for inhibitors of the murine GABA transporters mGAT3 and mGAT4.
abstract: Searching for potent and subtype selective parent structures of the murine gamma-aminobutyric acid (GABA) transporter subtypes mGAT3 and mGAT4 a series of amino acids was characterised in a uniform [3H]GABA uptake test system based on transiently expressed mGAT1-4. From several potent inhibitors showing IC50 values at mGAT3 and mGAT4 in the low microM range cis-4-aminocrotonic acid and (RS)-2,3-diaminopropionic acid turned out to be most subtype selective for these transporters. With (RS)-isoserine--a compound unknown as GAT inhibitor until now--one of the most potent amino acids selectively inhibiting mGAT3 and mGAT4 was found. Furthermore, (2-amino-1,3-thiazol-4-yl)acetic acid was identified as the first parent structure exhibiting a clear, though still moderate, selective inhibition of GABA uptake at mGAT3.
authors.affiliation: Department Pharmazie-Zentrum für Pharmaforschung-Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, D-81377 München, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kragler
authors.forename: Georg
authors.initials: G
authors.lastname: Höfner
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Wanner
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D050485:GABA Plasma Membrane Transport Proteins; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D014179:Neurotransmitter Uptake Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010957:Plasmids / Q000235:genetics; D011422:Propionates / Q000737:chemistry / Q000494:pharmacology; D012694:Serine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D014162:Transfection; D014316:Tritium; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000085:Acetates; D050485:GABA Plasma Membrane Transport Proteins; D006146:Guanidines; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D014179:Neurotransmitter Uptake Inhibitors; D011422:Propionates; D012694:Serine; D013844:Thiazoles; D014316:Tritium; D015091:beta-Alanine; D005680:gamma-Aminobutyric Acid; C079264:Slc6a11 protein, mouse; C490439:Slc6a12 protein, mouse; C493419:Slc6a13 protein, mouse; C072421:isoserine; C011757:2,3-diaminopropionic acid; C505034:(2-amino-1,3-thiazol-4-yl)acetic acid; C005775:guanidinopropionic acid