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

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journal contribution
posted on 26.02.2009, 00:00 by Anders A. Jensen, Mette N. Erichsen, Christina W. Nielsen, Tine B. Stensbøl, Jan Kehler, Lennart Bunch
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.