Kynurenic acid derivatives. Structure-activity relationships for excitatory amino acid antagonism and identification of potent and selective antagonists at the glycine site on the N-methyl-D-aspartate receptor

Abstract

Derivatives of the nonselective excitatory amino acid antagonist kynurenic acid (4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1) have been synthesized and evaluated for in vitro antagonist activity at the excitatory amino acid receptors sensitive to N-methyl-D-aspartic acid (NMDA), quisqualic acid (QUIS or AMPA), and kainic acid (KA). Introduction of substituents at the 5-, 7-, and 5,7-positions resulted in analogues having selective NMDA antagonist action, as a result of blockade of the glycine modulatory (or coagonist) site on the NMDA receptor. Regression analysis suggested a requirement for optimally sized, hydrophobic 5- and 7-substituents, with bulk tolerance being greater at the 5-position. Optimization led to the 5-iodo-7-chloro derivative (53), which is the most potent and selective glycine/NMDA antagonist to date (IC50 vs [3H]glycine binding, 32 nM; IC50's for other excitatory amino acid receptor sites, greater than 100 microM). Substitution of 1 at the 6-position resulted in compounds having selective non-NMDA antagonism and 8-substituted compounds were inactive at all receptors. The retention of glycine/NMDA antagonist activity in heterocyclic ring modified analogues, such as the oxanilide 69 and the 2-carboxybenzimidazole 70, suggests that the 4-oxo tautomer of 1 and its derivatives is required for activity. Structurally related quinoxaline-2,3-diones are also glycine/NMDA antagonists, but are not selective and are less potent than the 1 derivatives, and additionally show different structure-activity requirements for aromatic ring substitution. On the basis of these results, a model accounting for glycine receptor binding of the 1 derived antagonists is proposed, comprising (a) size-limited, hydrophobic binding of the benzene ring, (b) hydrogen-bond acceptance by the 4-oxo group, (c) hydrogen-bond donation by the 1-amino group, and (d) a Coulombic attraction of the 2-carboxylate. The model can also account for the binding of quinoxaline-2,3-diones, quinoxalic acids, and 2-carboxybenzimidazoles.

Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acid

“…Within this group, 7-chlorokynurenic acid (7-Cl-KYNA) and 5,7-dichlorokynurenic acid (5,7-Cl 2 -KYNA) are the prototypic agents and show superb potency and selectivity in vitro. 4 As a result of their low lipid solubility, these halogenated KYNA derivatives cross the bloodbrain barrier poorly and show minimal penetration into the brain following systemic administration. 3 An alternative means of delivering 7-Cl-KYNA or 5,7-Cl 2 KYNA to the brain might be through their precursors, L-4-chlorokynurenine (4-Cl-KYN) and L-4,6-dichlorokynurenine (4,6-Cl 2 -KYN).…”

Synthesis of 3,4-dihydro-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxides and their evaluation as ligands for NMDA receptor glycine binding site

“…Our first synthesized 3,4-dihydrobenzothiazine 18b showed a considerable activity at 10 mM concentration, replacing ca 50% of radioligand. It should be noted that the reference compound of kynurenic acid with two halogen atoms in positions 6 and 8 (DCKA), showed higher activity than its 6-monochloro analogue 13 . In our case, 6,8-dichlorobenzothiazine 18b and monochloro derivative 18a displayed comparable activities.…”

“…, we focused on information from the early studies of 5,7-dichlorokynurenic acid (I, DCKA) 13 . It has been shown that 4-O-substitution dramatically reduced the activity of the compounds.…”

“…However, combination of sulfonamide and carboxy functions has already been known to be of great importance in this type of structures 15,16 . Both modifications described above have been designed based on a common pharmacophore model of 5,7-dichlorokynurenic acid (I, DCKA) 13 , including NH as a presumable H-donor and specific substituents as in structure 1. The surprising loss of activity, when the sulfonyl group was replaced by carbonyl 15 , prompted us to evaluate carba-analogs III possessing the same sulfonamide fragment and carboxyl group as crucial pharmacophores.…”

Dopamine receptor activation reveals a novel, kynurenate-sensitive component of striatal N-methyl-d-aspartate neurotoxicity

“…KYNA inhibits the glutamate binding site of the NMDA receptor competitively with an IC 50 of approximately 200 μM (Ganong and Cotman, 1986) and has a similar, low affinity to non-NMDA receptors (Leeson et al, 1991). Inhibition of these sites accounts for the widely used classification of KYNA as a "broad spectrum" antagonist of excitatory amino acid receptors and explains why the local application of millimolar concentrations of KYNA effectively blocks both NMDA-and kainate-mediated excitotoxicity (Foster et al, 1984).…”