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

ABSTRACT: 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 24h. In addition, one of the derivatives (7-22) enhanced EAAT2 levels 3.5-3.9-fold after 24h with an EC(50) of 0.5 ?M.

SUBMITTER: Xing X

PROVIDER: S-EPMC3172717 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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

Xing Xuechao X Chang Ling-Chu LC Kong Qiongman Q Colton Craig K CK Lai Liching L Glicksman Marcie A MA Lin Chien-Liang Glenn CL Cuny Gregory D GD

Bioorganic & medicinal chemistry letters 20110808 19

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-fol ...[more]

PMID: 21875806

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