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Bioorg Med Chem Lett. 2011 Oct 1;21(19):5774-7. doi: 10.1016/j.bmcl.2011.08.009. Epub 2011 Aug 8.

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

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  • 1Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne St., Cambridge, MA 02139, USA.

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 μM 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 μM.

Copyright © 2011 Elsevier Ltd. All rights reserved.

PMID:
21875806
[PubMed - indexed for MEDLINE]
PMCID:
PMC3172717
Free PMC Article
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