5-Phosphonomethylquinoxalinediones as competitive NMDA receptor antagonists with a preference for the human 1A/2A, rather than 1A/2B receptor composition.
NMDA antagonists derived from 5-phosphonomethyl-1,4-dihydroquinoxaline-2,3-dione (3a) are potent anticonvulsant agents, and display strong protective effects in the electroshock-induced convulsion assay in mice. Their preference for the human NMDAR 1A/2A over 1A/2B subunit composition was optimized, leading to (1RS,1'S)-PEAQX (9r), which shows a >100-fold selectivity.
Auberson
Yves P
YP
Novartis Pharma AG, Klybeckstrasse 141, 4002 Basel, Switzerland. yves.auberson@pharma.novartis.com
Allgeier
Hans
H
Bischoff
Serge
S
Lingenhoehl
Kurt
K
Moretti
Robert
R
Schmutz
Markus
M
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001667:Binding, Competitive; D004558:Electric Stimulation; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D000927:Anticonvulsants; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor