160853-05-4Relevant academic research and scientific papers
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
Cai, Sui Xiong,Zhou, Zhang-Lin,Huang, Jin-Cheng,Whittemore, Edward R.,Egbuwoku, Zizi O.,Lü, Yixin,Hawkinson, Jon E.,Woodward, Richard M.,Weber, Eckard,Keana, John F. W.
, p. 3248 - 3255 (2007/10/03)
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 K(b) of 1-2 nM for NMDA receptors expressed in Xenopus oocytes. 5,6,7-Trichloro-QTO also had a K(b) 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.
