title: Discovery of the first selective inhibitor of excitatory amino acid transporter subtype 1.
abstract: The discovery of the first class of subtype-selective inhibitors of the human excitatory amino acid transporter subtype 1 (EAAT1) and its rat orthologue GLAST is reported. An opening structure-activity relationship of 25 analogues is presented that addresses the influence of substitutions at the 4- and 7-positions of the parental skeleton 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile. The most potent analogue 1o displays high nanomolar inhibitory activity at EAAT1 and a >400-fold selectivity over EAAT2 and EAAT3, making it a highly valuable pharmacological tool.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark. aaj@farma.ku.dk
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.forename: Mette N
authors.initials: MN
authors.lastname: Erichsen
authors.forename: Christina W
authors.initials: CW
authors.lastname: Nielsen
authors.forename: Tine B
authors.initials: TB
authors.lastname: Stensbøl
authors.forename: Jan
authors.initials: J
authors.lastname: Kehler
authors.forename: Lennart
authors.initials: L
authors.lastname: Bunch
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D027341:Excitatory Amino Acid Transporter 1 / Q000037:antagonists & inhibitors*; D006801:Humans; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001578:Benzopyrans; D027341:Excitatory Amino Acid Transporter 1; D009570:Nitriles; C493394:SLC1A3 protein, human; C493392:Slc1a3 protein, rat