Structure–activity relationship study of pyridazine derivatives as glutamate transporter EAAT2 activators


Excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter and functions to remove glutamate from synapses. A thiopyridazine derivative has been found to increase EAAT2 protein levels in astrocytes. A structure–activity relationship study revealed that several components of the molecule were required for activity, such as the thioether and pyridazine. Modification of the benzylthioether resulted in several derivatives (7-13, 7-15 and 7-17) that enhanced EAAT2 levels by >6-fold at concentrations <5 ?M after 24 h. In addition, one of the derivatives (7-22) enhanced EAAT2 levels 3.5–3.9-fold after 24 h with an EC50 of 0.5 ?M.



Excitatory amino acid transporter 2, glutamate, pyridazines, excitotoxcity


Copyright 2011 Bioorganic and Medicinal Chemistry Letters. This is a post-print version of a published paper that is available at: Recommended citation: Xing, Xuechao, Ling-Chu Chang, Qiongman Kong, Craig K. Colton, Liching Lai, Marcie A. Glicksman, Chien-Liang Glenn Lin, and Gregory D. Cuny. "Structure–activity relationship study of pyridazine derivatives as glutamate transporter EAAT2 activators." Bioorganic & medicinal chemistry letters 21, no. 19 (2011): 5774-5777. doi: 10.1016/j.bmcl.2011.08.009. This item has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.