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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:21

Article

Xing, Xuechao^1,2  Chang, Ling-Chu³  Kong, Qiongman³  Colton, Craig K.³  Lai, Liching³  Glicksman, Marcie A.^1,2  Lin, Chien-Liang Glenn³  Cuny, Gregory D.^1,2 

[1] Brigham & Womens Hosp, Lab Drug Discovery Neurodegenerat, Harvard NeuroDiscovery Ctr, Cambridge, MA 02139 USA

[2] Harvard Univ, Sch Med, Cambridge, MA 02139 USA

[3] Ohio State Univ, Dept Neurosci, Columbus, OH 43210 USA

关键词: Excitatory amino acid transporter 2;    Glutamate;    Pyridazines;    Excitotoxicity;   

DOI  :  10.1016/j.bmcl.2011.08.009

来源: Elsevier

【 摘 要 】

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 mu 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 mu M. (C) 2011 Elsevier Ltd. All rights reserved.

【 授权许可】

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