title: Synthesis and SAR of novel di- and trisubstituted 1,4-dihydroquinoxaline-2,3-diones related to licostinel (Acea 1021) as NMDA/glycine site antagonists.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Oregon, Eugene, OR 97403, USA.
authors.forename: Zhang-Lin
authors.initials: ZL
authors.lastname: Zhou
authors.forename: Sunil M
authors.initials: SM
authors.lastname: Kher
authors.forename: Sui Xiong
authors.initials: SX
authors.lastname: Cai
authors.forename: Edward R
authors.initials: ER
authors.lastname: Whittemore
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Espitia
authors.forename: Jon E
authors.initials: JE
authors.lastname: Hawkinson
authors.forename: Minhtam
authors.initials: M
authors.lastname: Tran
authors.forename: Richard M
authors.initials: RM
authors.lastname: Woodward
authors.forename: Eckard
authors.initials: E
authors.lastname: Weber
authors.forename: John F W
authors.initials: JF
authors.lastname: Keana
mesh_terms: 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
chemical_list: D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C092062:licostinel; D007736:Kynurenic Acid; C066192:5,7-dichlorokynurenic acid; D005998:Glycine