Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 21, Issue 19, Pages 5774-5777Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.08.009
Keywords
Excitatory amino acid transporter 2; Glutamate; Pyridazines; Excitotoxicity
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Funding
- National Institutes of Health [U24 NS04933901, R01 NS064275]
- Harvard NeuroDiscovery Center
- ALS Therapy Alliance, Inc
- ALS
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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.
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