Discovery of the First Selective Inhibitor of Excitatory Amino Acid Transporter Subtype 1

• Published in: Journal of medicinal chemistry Vol. 52; no. 4; pp. 912 - 915
• Main Authors: Jensen, Anders A, Erichsen, Mette N, Nielsen, Christina W, Stensbøl, Tine B, Kehler, Jan, Bunch, Lennart
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.02.2009; Amer Chemical Soc
• Subjects: Animals; Benzopyrans - chemistry; Benzopyrans - pharmacology; Biological and medical sciences; Chemistry, Medicinal; Drug Discovery; Excitatory Amino Acid Transporter 1 - antagonists & inhibitors; Glutamatergic system (aspartate and other excitatory aminoacids); Humans; Life Sciences & Biomedicine; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Nitriles - chemistry; Nitriles - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Science & Technology; Structure-Activity Relationship; DESIGN; GLUTAMATE TRANSPORTERS; ONE-POT SYNTHESIS; PHARMACOLOGICAL CHARACTERIZATION; AQUEOUS-MEDIA; EAAT1; BROMIDE; RECEPTORS; DERIVATIVES; BRAIN; Human; Embryo; Nitrile; Biological transport; Selectivity; Naphthalene derivatives; In vitro; Kidney; Cell line; Structure activity relation; Excitatory aminoacid; Inhibitor; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm8013458

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.