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.
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.
Cai
S X
SX
CoCensys Inc., Irvine, California 92618, USA.
Zhou
Z L
ZL
Huang
J C
JC
Whittemore
E R
ER
Egbuwoku
Z O
ZO
Lü
Y
Y
Hawkinson
J E
JE
Woodward
R M
RM
Weber
E
E
Keana
J F
JF
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
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