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

X Xing, LC Chang, Q Kong, CK Colton, L Lai… - Bioorganic & medicinal …, 2011 - Elsevier
X Xing, LC Chang, Q Kong, CK Colton, L Lai, MA Glicksman, CLG Lin, GD Cuny
Bioorganic & medicinal chemistry letters, 2011Elsevier
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< 5μM after 24h. In …
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 <5μM after 24h. In addition, one of the derivatives (7-22) enhanced EAAT2 levels 3.5–3.9-fold after 24h with an EC50 of 0.5μM.
Elsevier