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.
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.
Greenfield
Alexander
A
Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. greenfa@wyeth.com
Grosanu
Cristina
C
Dunlop
John
J
McIlvain
Beal
B
Carrick
Tikva
T
Jow
Brian
B
Lu
Qiang
Q
Kowal
Dianne
D
Williams
John
J
Butera
John
J
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*
D027342:Excitatory Amino Acid Transporter 2; D005449:Fluorenes; D011422:Propionates; D004986:Ether; D015091:beta-Alanine; D001224:Aspartic Acid; C041509:fluorene; C029658:propionic acid