title: Synthesis and biological activities of aryl-ether-, biaryl-, and fluorene-aspartic acid and diaminopropionic acid analogs as potent inhibitors of the high-affinity glutamate transporter EAAT-2.
abstract: Excitatory amino acid transporters (EAATs) play a pivotal role in maintaining glutamate homeostasis in the mammalian central nervous system, with the EAAT-2 subtype thought to be responsible for the bulk of the glutamate uptake in forebrain regions. A complete elucidation of the functional role of EAAT-2 has been hampered by the lack of potent and selective pharmacological tools. In this study, we describe the synthesis and biological activities of novel aryl-ether, biaryl-, and fluorene-aspartic acid and diaminopropionic acid analogs as potent inhibitors of EAAT-2. Compound (16) represents one of the most potent (IC50=85+/-5 nM) and selective inhibitors of EAAT-2 identified to date.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. greenfa@wyeth.com
authors.forename: Alexander
authors.initials: A
authors.lastname: Greenfield
authors.forename: Cristina
authors.initials: C
authors.lastname: Grosanu
authors.forename: John
authors.initials: J
authors.lastname: Dunlop
authors.forename: Beal
authors.initials: B
authors.lastname: McIlvain
authors.forename: Tikva
authors.initials: T
authors.lastname: Carrick
authors.forename: Brian
authors.initials: B
authors.lastname: Jow
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lu
authors.forename: Dianne
authors.initials: D
authors.lastname: Kowal
authors.forename: John
authors.initials: J
authors.lastname: Williams
authors.forename: John
authors.initials: J
authors.lastname: Butera
mesh_terms: D001224:Aspartic Acid / Q000737:chemistry*; D001692:Biological Transport / Q000187:drug effects; D004986:Ether / Q000737:chemistry*; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005449:Fluorenes / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011422:Propionates / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D005449:Fluorenes; D011422:Propionates; D004986:Ether; D015091:beta-Alanine; D001224:Aspartic Acid; C041509:fluorene; C029658:propionic acid