Synthesis and SAR of novel di- and trisubstituted 1,4-dihydroquinoxaline-2,3-diones related to licostinel (Acea 1021) as NMDA/glycine site antagonists.
A series of novel di- and trisubstituted 1,4-dihydroquinoxaline-2,3-diones (QXs) related to licostinel (Acea 1021) was synthesized and evaluated as antagonists for the glycine site of the N-methyl-D-asparate (NMDA) receptor. The in vitro potency of these antagonists was determined by displacement of the glycine site radioligand [(3)H]-5,7-dichlorokynurenic acid ([(3)H]DCKA) in rat brain cortical membranes. Structure-activity relationship studies indicate that a cyano group is a good replacement for the nitro group in the 5-position of licostinel while 5-carboxy, 5-ester, 5-ketone and 5-amide derivatives showed reduced potency. 5,6-Cyclized analogues of licostinel also showed significantly reduced potency. Among the trisubstituted QXs investigated, 5-cyano-6,7-dichloro QX and 5-cyano-7-chloro-6-methyl QX are the most potent with IC(50) values of 32 nM and 26 nM, respectively.
Zhou
Zhang-Lin
ZL
Department of Chemistry, University of Oregon, Eugene, OR 97403, USA.
Kher
Sunil M
SM
Cai
Sui Xiong
SX
Whittemore
Edward R
ER
Espitia
Stephen A
SA
Hawkinson
Jon E
JE
Tran
Minhtam
M
Woodward
Richard M
RM
Weber
Eckard
E
Keana
John F W
JF
D000818:Animals; D001665:Binding Sites; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D005998:Glycine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C092062:licostinel; D007736:Kynurenic Acid; C066192:5,7-dichlorokynurenic acid; D005998:Glycine