Kynurenic acid derivatives

Kynurenic acid is the mother substance of a group of compounds with quinoline ring system. Most of these substances carry a carboxy group in position 2 and a hydroxy group in position 4. Additional hydroxy groups may be present. 

Kynurenic acid derivatives are formed in microorganisms, plants, and animals. 

The precursors of kynurenic acid and its derivatives are L-kynurenine and hydroxylated L-kynurenines, like 3-hydroxy-L-kynurenine (D 21), 5-hydroxy-L-kynurenine (derived from 5-hydroxy-L-tryptophan, D 21), 3,4-dihydroxy-L-kynurenine, etc. Quinaldic acid and related substances not hydroxylated in position 4 are derived from the hydroxylated compounds in animals. The reduction is probably performed by the microorganisms living in the intestinal tract. 4-Hydroxyquinoline and related substances devoid of the carboxy group in position 2 are derived from kynuramine. 

Certain microorganisms degrade L-tryptophan (in some cases also D-trypto-phan) via kynurenic acid to compounds of primary metabolism (Fig. 265, quinolinic pathway of tryptophan degradation, in contrast to the aromatic pathway via 3-hydroxyanthranilic acid shown in Fig. 244). 

In mammals, birds, insects, and some plants, compounds of the kynurenic acid group are end products of tryptophan metabolism. They are either excreted with the urine (E 1) or are accumulated in the organism. 8-Hydroxyquinaldic acid methyl ester is a feeding deterrent and aseptic of certain water beetles (E 5.1). 

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Derivatization of kynurenic acid leads to far more potent and selective antagonists such as 7-chloro-kynurenic acid or 5,7-dichlorokynurenic acid (Kemp et al., 1988 Baron et al., 1990) which have been shown to inhibit glycine-induced tailflick facilitation (i.e attenuation of glycine-induced hyperalgesia) or the late phase of formalin-induced nociception when given intrathecally (Kolhekar et al., 1994, Chapman et al., 1995). Nevertheless kynurenic acid derivatives are still hampered by a poor blood - brain barrier penetration and hence a low CNS availability. 

Chlorokynurenic acid 5,7-Dichlorokynurenic acid Scheme 3 Structures of kynurenic acid derivatives. 

Stone, T. W. Development and therapeutic potential of kynurenic acid and kynurenine derivatives for neuroprotection, Trends Pharmacol. Sci. 2000, 21, 149-154. 

Stone TW (2000) Development and therapeutic potential of kynurenic acid and kynurenine derivatives for neuroprotection. Trends Pharmacol Sci 21 149-154 Suardiaz M, Estivill-Terms G, Goicoechea C, Bilbao A, Rodriguez de Fonseca F (2007) Analgesic properties of oleoylethanolamide (OEA) in visceral and inflammatory pain. Pain 133 99-110... 

It was only many years after the discovery of tryptophan that a plausible degradative pathway could first be outlined, but during this early period a few tryptophan metabolites were identified. The long-known (559) kynurenic acid (structure, diagram 20 cf. 408) was shown in 1904 to be derived from tryptophan (220), but the considerable amount of work on kynurenic acid formation (reviewed by Neubauer, 637) gave few useful results. Neubauer (637), however, made the plausible (and correct) suggestion that it was derived from o-aminobenzoylpyruvic acid (structure, diagram 20). 

Kynurenic acid, xanthurenic acid, and derivatives (diagram 19)... 

The nicotinic acid pathway potentially gives rise to a number of excretion products, largely due to side reactions, such as anthranilic acid, kynurenic acid, and xanthurenic acid, but normally these are excreted in, at most, small amounts. Presumably, therefore, the greater part of ingested tiyp-tophan should give nicotinic acid or simple derivatives. But normal excretion of nicotinic acid and its derivatives is in any case low, and when... 

Weil-Fugazza38 reviewed some endogenous kynurenine derivatives (e.g., kynurenic acid and quinolinic acid) and their association with pain. They concluded that kynurenine derivatives may play an important role in the mechanisms of the transmission of nociceptive messages at the level of the spinal cord. They speculated that pharmacologic studies of drugs modulating the kynurenine metabolism initiated for the treatment of neurologic dysfunctions could also be useful for therapy of pain. Specifically, a number of studies support the hypothesis that the kynurenine pathway is involved in the modulation of the activity of the excitatory amino acid transmitters in the CNS.40-41... 

Wu H-Q, Pereira EFR, Bruno JP, Pellicciari R, Albuquerque EX, Schwarcz R (2010) The astrocyte-derived a7 nicotinic receptor antagonist kynurenic acid controls extracellular glutamate levels in the prefrontal cortex. J Mol Neurosci 40 204-210... 

Our knowledge of alkaloids in animals is scant. The so-called protoalkaloids (biogenic amines and their derivatives) are widespread in lower animals (194, 195), and the parallelism between plant and animal metabolism is extensive. Betaines, methylated purines (e.g., paraxan-thine (VI) ), derivatives of histidine (spinacine (VII) of the shark), and kynurenic acid (VIII) are not rare in animals. The animal alkaloids, with the exception of samandarine (Vol. V, p. 321), are characterized as weak bases this is perhaps of importance for their excretion. 

One particularly effective example of the use of IsoStar was in the design of inhibitors for the N-methyl D-aspartate (NMDA) receptor. Here two known inhibitors, kynurenic acid and arylideno-imidazolinonoyl-glycine, were decomposed into functional groups and their interaction patterns analyzed in IsoStar. Armed with this information, the binding mode was rationalized and a simple pharmacophore of the NMDA receptor was created [36]. The pharmacophore was able to explain activity data of compounds derived from the original inhibitors modified by esterification [37], and was also able to inspire a new set of inhibitors with improved pharmacochemical properties [38]. 

From a comparison of the growth response of Neurospora to kynurenic and xanthurenic acids with that of a number of nicotinic acid derivatives, it was concluded that the pyridine ring of nicotinic acid is not formed by kynurenine first being converted to kynurenic acid or xanthurenic acid, and this in turn being followed by the oxidation of the benzene ring moiety to yield nicotinic acid as a residium. ... 

Kynurenine, which is formed from the formyl derivative by the action of formamidase, may be metabolized to a quinoline derivative, kynurenic acid. Alanine may be removed from kynurenine by kynureninase to form anthranilic acid. 

We shall adopt this convention and therefore exclude the last-mentioned groups of acids from this review and shall furthermore exclude other nitrogen-containing acids, such as pyrrolidone-carboxylic acid, indoles, and other metabolites of tryptophan (e.g., anthranilic, hydroxyan-thranilic, kynurenic, xanthurenic, and nicotinic acids), imidazolic metabolites or histidine (e.g., fl-imidazolylpyruvic and urocanic acids), acidic guanidine derivatives, and carbamylated acids, as well as acidic com-... 

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