7-Chlorokynurenic acid sodium salt

Substituted quinolines as inhibitors of L-glutamate transport into synaptic vesicles.[Pubmed:9776380]

Neuropharmacology. 1998 Jul;37(7):839-46.

This study investigated the structure-activity relationships and kinetic properties of a library of kynurenate analogues as inhibitors of 3H-L-glutamate transport into rat forebrain synaptic vesicles. The lack of inhibitory activity observed with the majority of the monocyclic pyridine derivatives suggested that the second aromatic ring of the quinoline-based compounds played a significant role in binding to the transporter. A total of two kynurenate derivatives, xanthurenate and 7-chloro-kynurenate, differing only in the carbocyclic ring substituents, were identified as potent competitive inhibitors, exhibiting Ki values of 0.19 and 0.59 mM, respectively. The Km value for L-glutamate was found to be 2.46 mM. Parallel experiments demonstrated that while none of the kynurenate analogues tested effectively inhibited the synaptosomal transport of 3H-D-aspartate, some cross-reactivity was observed with the EAA ionotropic receptors. Molecular modeling studies were carried out with the identified inhibitors and glutamate in an attempt to preliminarily define the pharmacophore of the vesicular transporter. It is hypothesized that the ability of the kynurenate analogues to bind to the transporter may be tied to the capacity of the quinoline carbocyclic ring to mimic the negative charge of the gamma-carboxylate of glutamate. A total of two low energy solution conformers of glutamate were identified that exhibited marked functional group overlap with the most potent inhibitor, xanthurenate. These results help to further refine the pharmacological specificity of the glutamate binding site on the vesicular transporter and identify a series of inhibitors with which to investigate transporter function.

Behavioral and neurochemical actions of the strychnine-insensitive glycine receptor antagonist, 7-chlorokynurenate, in rats.[Pubmed:7498252]

Eur J Pharmacol. 1995 Jun 23;280(1):37-45.

The present study investigated if blockade of the modulatory glycine receptor of the NMDA receptor complex influences the expression of behavior (sniffing stereotypy and locomotion) and dopamine metabolism in rats as it has been shown for NMDA receptor antagonists. The glycine receptor antagonist, 7-chlorokynurenate (7-chloro-4-hydroxyquinoline-2-carboxylic acid), induced a dose-dependent sniffing stereotypy but had no effect on locomotion when it was given i.c.v. The glycine receptor agonist, D-cycloserine (D-4-amino-3-isoxazolidinone), antagonized the sniffing stereotypy. 7-Chlorokynurenate had no influence on dopamine metabolism in the striatum and the nucleus accumbens, but moderately decreased the metabolism in the prefrontal cortex. Comparison of behavioral and neurochemical outcomes suggests that the failure to induce locomotion correlates with the unchanged dopamine metabolism in the basal ganglia, while sniffing stereotypy does not. These results show that blockade of the glycine receptor of the NMDA receptor complex induces a behavioral and neurochemical profile similar to that of competitive NMDA receptor antagonists.

7-Chlorokynurenic acid sodium salt (7-CKA sodium salt) is a potent and selective antagonist of the glycine B coagonist site of the N-methyl-D-aspartate (NMDA) receptor (IC50=0.56 μM). 7-Chlorokynurenic acid sodium salt is also a potent inhibitor of the reuptake of glutamate into synaptic vesicles with a Ki of 0.59 μM. 7-Chlorokynurenic acid sodium salt has potent antinociceptive actions after neuraxial delivery.

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