title: Synthesis and structure-activity relationships of 1,2,3,4-tetrahydroquinoline-2,3,4-trione 3-oximes: novel and highly potent antagonists for NMDA receptor glycine site.
abstract: A series of 1,2,3,4-tetrahydroquinoline-2,3,4-trione 3-oximes (QTOs) was synthesized and evaluated for antagonism of NMDA receptor glycine site. Glycine site affinity was determined using a [3H]DCKA binding assay in rat brain membranes and electrophysiologically in Xenopus oocytes expressing 1a/2C subunits of cloned rat NMDA receptors. Selected compounds were also assayed for antagonism of AMPA receptors in Xenopus oocytes expressing rat brain poly-(A)+RNA. QTOs were prepared by nitrosation of 2,4-quinolinediols. Structure-activity studies indicated that substitutions in the 5-, 6-, and 7-positions increase potency, whereas substitution in the 8-position causes a decrease in potency. Among the derivatives evaluated, 5,6,7-trichloro-QTO was the most potent antagonist with an IC50 of 7 nM in the [3H]DCKA binding assay and a Kb of 1-2 nM for NMDA receptors expressed in Xenopus oocytes. 5,6,7-Trichloro-QTO also had a Kb of 180 nM for AMPA receptors in electrophysiological assays. The SAR of QTOs was compared with the SAR of 1,4-dihydroquinoxaline-2,3-diones (QXs). For compounds with the same benzene ring substitution pattern, QTOs were generally 5-10 times more potent than the corresponding QXs. QTOs represent a new class of inhibitors of the NMDA receptor which, when appropriately substituted, are among the most potent glycine site antagonists known.
authors.affiliation: CoCensys Inc., Irvine, California 92618, USA.
authors.forename: S X
authors.initials: SX
authors.lastname: Cai
authors.forename: Z L
authors.initials: ZL
authors.lastname: Zhou
authors.forename: J C
authors.initials: JC
authors.lastname: Huang
authors.forename: E R
authors.initials: ER
authors.lastname: Whittemore
authors.forename: Z O
authors.initials: ZO
authors.lastname: Egbuwoku
authors.forename: Y
authors.initials: Y
authors.lastname: Lü
authors.forename: J E
authors.initials: JE
authors.lastname: Hawkinson
authors.forename: R M
authors.initials: RM
authors.lastname: Woodward
authors.forename: E
authors.initials: E
authors.lastname: Weber
authors.forename: J F
authors.initials: JF
authors.lastname: Keana
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003001:Cloning, Molecular; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005998:Glycine; D007700:Kinetics; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D014981:Xenopus
chemical_list: D018691:Excitatory Amino Acid Antagonists; D010091:Oximes; D011804:Quinolines; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D007736:Kynurenic Acid; C066192:5,7-dichlorokynurenic acid; D005998:Glycine