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.

Structural Model of the N-Methyl-D-aspartate Receptor Glycine Site Probed by Site-directed Chemical Coupling

“…This is consistent with previous ligand modification and site-directed mutagenesis studies. Substitutions on the quinoline ring system have been found to drastically reduce binding affinity (32)(33)(34), and mutations in the surrounding loops are known to lower glycine efficacy (15). Although ligands carrying a reactive group in their 7-position did not react with cysteines introduced in polypeptide positions 501 and 502, m 1 -NCS carrying the reactive m-phenylisothiocyanate substituent at the 3-position of the quinoline ring, i.e.…”

Quinoline Oximes: Synthesis, Reactions, and Biological Activity. (Review)

“…The 1,2,3,4-tetrahydroquinoline-2,2,4-trione oximes 29 acted as antagonists of NDMA in glycine receptors [35,137,138]. These compounds were used as agents against neurodegenerative diseases (e.g., Alzheimer's disease).…”

“…The oxime of 1,2,3,4-tetrahydroacridine (23) was successfully obtained in this way from the corresponding acridine 24 in the isoamyl nitrite/butyllithium/ether system [31]. The quinoline-2,4-diones 28 are easily nitrosated in the presence of sodium nitrite [33][34][35]. The products -1,2,3,4-tetrahydroquinoline-2,3,4-trione 3-oximes 29 -have been used as bactericides [33], exhibited antiviral activity [34], and were studied as agents that affect central nervous system [35].…”

“…The reaction of 8-hydroxy-7-iodo-5-quinolinesulfonic acid (35) with sodium nitrite in the presence of aqueous hydrochloric acid leads to the tautomeric forms of the product 36 [39]. 3-(2-Quinolylamino)-1,2,5-oxadiazoles 37 rearrange in the presence of potassium butoxide to the oximes of 2-acyl-1,2,4-triazolo[1,5-a]quinolines 38 (yields 66-70%) [40].…”

Experimental and theoretical NMR study of selected oxocarboxylic acid oximes

“…The oximes may also be useful for the treatment of rheumatoid arthritis [copper(II) diaminodioxime complexes], 9 prostate cancer (inhibitors of P450 17 and 5˛-reductase) 10 and Alzheimer's disease. 11 As a first step in understanding their coordination to metal ions, knowledge of the structure of the ligands themselves is necessary. This paper presents our investigation of the structures of three oxocarboxylic oxime acids with potential bioactivity: 2-hydroxyiminopropanoic acid (1) and its derivatives 2-(4-methylthiazol-2-yl)-2-(hydroxyimino)acetic acid (2) and 2-cyano-2-(hydroxyimino)acetic acid (3) (Scheme 1).…”