title: 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 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.
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne St., Cambridge, MA 02139, USA.
authors.forename: Xuechao
authors.initials: X
authors.lastname: Xing
authors.forename: Ling-Chu
authors.initials: LC
authors.lastname: Chang
authors.forename: Qiongman
authors.initials: Q
authors.lastname: Kong
authors.forename: Craig K
authors.initials: CK
authors.lastname: Colton
authors.forename: Liching
authors.initials: L
authors.lastname: Lai
authors.forename: Marcie A
authors.initials: MA
authors.lastname: Glicksman
authors.forename: Chien-Liang Glenn
authors.initials: CL
authors.lastname: Lin
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
mesh_terms: D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D027342:Excitatory Amino Acid Transporter 2 / Q000819:agonists* / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D005971:Glutamates; D011724:Pyridazines