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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Biological Transport
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Excitatory Amino Acid Transporter 2 / agonists*
  • Excitatory Amino Acid Transporter 2 / metabolism
  • Glutamates / metabolism
  • Pyridazines / chemical synthesis*
  • Pyridazines / chemistry
  • Pyridazines / pharmacology*
  • Structure-Activity Relationship


  • Excitatory Amino Acid Transporter 2
  • Glutamates
  • Pyridazines