PT  - JOURNAL ARTICLE
AU  - Dunlop, John
AU  - McIlvain, H. Beal
AU  - Carrick, Tikva A.
AU  - Jow, Brian
AU  - Lu, Qiang
AU  - Kowal, Dianne
AU  - Lin, Steven
AU  - Greenfield, Alexander
AU  - Grosanu, Cristina
AU  - Fan, Kristi
AU  - Petroski, Robert
AU  - Williams, John
AU  - Foster, Alan
AU  - Butera, John
TI  - Characterization of Novel Aryl-Ether, Biaryl, and Fluorene Aspartic Acid and Diaminopropionic Acid Analogs as Potent Inhibitors of the High-Affinity Glutamate Transporter EAAT2
AID  - 10.1124/mol.105.012005
DP  - 2005 Oct 01
TA  - Molecular Pharmacology
PG  - 974--982
VI  - 68
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/68/4/974.short
4100  - http://molpharm.aspetjournals.org/content/68/4/974.full
SO  - Mol Pharmacol2005 Oct 01; 68
AB  - In this study, we describe the pharmacological characterization of novel aryl-ether, biaryl, and fluorene aspartic acid and diaminopropionic acid analogs as potent inhibitors of EAAT2, the predominant glutamate transporter in forebrain regions. The rank order of potency determined for the inhibition of human EAAT2 was N4-[4-(2-bromo-4,5-difluorophenoxy)phenyl]-l-asparagine (WAY-213613) (IC50 = 85 ± 5 nM) > N4-(2′-methyl-1,1′-biphenyl-4-yl)-l-asparagine (WAY-213394) (IC50 = 145 ± 22 nM) = N4-[7-(trifluoromethyl)-9H-fluoren-2-yl]-l-asparagine (WAY-212922) (IC50 = 157 ± 11 nM) = 3-{[(4′-chloro-2-methyl-1,1′-biphenyl-4-yl)carbonyl]amino}-l-alanine (WAY-211686) (IC50 = 190 ± 10 nM). WAY-213613 was the most selective of the compounds examined, with IC50 values for inhibition of EAAT1 and EAAT3 of 5 and 3.8 μM, respectively, corresponding to a 59- and 45-fold selectivity toward EAAT2. An identical rank order of potency [WAY-213613 (35 ± 7 nM) > WAY-213394 (92 ± 13 nM) = WAY-212922 (95 ± 8 nM) = WAY-211686 (101 ± 20 nM)] was observed for the inhibition of glutamate uptake in rat cortical synaptosomes, consistent with the predominant contribution of EAAT2 to this activity. Kinetic studies with each of the compounds in synaptosomes revealed a competitive mechanism of inhibition. All compounds were determined to be nonsubstrates by evaluating both the stimulation of currents in EAAT2-injected oocytes and the heteroexchange of d-[3H]aspartate from cortical synaptosomes. WAY-213613 represents the most potent and selective inhibitor of EAAT2 identified to date. Taken in combination with its selectivity over ionotropic and metabotropic glutamate receptors, this compound represents a potential tool for the further elucidation of EAAT2 function.