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Kynurenine pathway inhibition as a therapeutic strategy for neuroprotection

Trevor W Stone1, Caroline M Forrest1, L Gail Darlington2


Institute for Neuroscience and Psychology,

College of Medical, Veterinary & Life Sciences, West Medical Building, University of Glasgow, Glasgow G12 8QQ, U.K. and

Epsom General Hospital

Epsom Surrey KT18 7EG

Article type

: Minireview

Running title:Kynurenines and neuronal viability

Correspondence:Prof. T W Stone, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK

This is an Accepted Article that has been peer-reviewed and approved for publication in the FEBS Journal, but has yet to undergo copy-editing and proof correction. Please cite this article as an “Accepted Article”; doi: 10.1111/j.1742-4658.2012.08487.x

Key-words:Tryptophan; kynurenine; quinolinic acid; kynurenic acid; neurodegeneration; neuroprotection;

Abstract The oxidative pathway for the metabolism of tryptophan along the kynurenine pathway generates quinolinic acid, an agonist at N-methyl-D-aspartate (NMDA) receptors, as well as kynurenic acid which is an antagonist at glutamate and nicotinic receptors. The pathway has become recognised as a key player in the mechanisms of neuronal damage and neurodegenerative disorders. As a result, manipulation of the pathway, so that the balance between the levels of components of the pathway can be modified, has become an attractive target for the development of pharmacological agents with the potential to treat those disorders. This review summarises some of the relevant background information on the pathway itself before identifying some of the chemical strategies for its modification, with examples of their successful application in animal models of infection, stroke, traumatic brain damage, cerebral malaria and cerebral trypanosomiasis.

Key-words:Tryptophan; kynurenine; quinolinic acid; kynurenic acid; neurodegeneration; neuroprotection;

Abbreviations AA: anthranilic acid AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid. CNS : central nervous system CSF: cerebrospinal fluid FCE28833A: 3,4-dichlorobenzoylalanine 3HAA: 3-hydroxyanthranilic acid IDO: indoleamine-2,3-dioxygenase IL-1β : interleukin-1β KAT: kynurenine aminotransferase KMO: kynurenine-3-monoxygenase L689,560: 2-carboxy-5,7-dichloro-4-[[(N-phenylamino)-carbonyl]amino]-1,2,3,4tetrahydroquinoline L701,252: 4-hydroxy-3-(cyclopropylcarbonyl)-7-chloroquinoline-2(1H)-one L701,324: 4-hydroxy-7-chloro-3-(3-phenyloxy)phenyl-quinoline-2(1H)-one MDL 100,748: 4-[(carboxymethyl)amino]-5,7-dichloroquinoline-2-carboxylic acid MDL29,951: 3-(4,6-dichloro-2-carboxyindole-3-yl)propionic acid MPP+ : 1-methyl-phenylpyridinium. NAD: nicotinamide adenine dinucleotide NMDA: N-methyl-D-aspartate Ro61-8048: 3,4-dimethoxy-N-[4-(3-nitrophenyl)-thiazol-2-yl]-benzenesulfonamide TDO: tryptophan-2,3-dioxygenase Th cells: T helper cells ZD9379: 7-chloro-4-hydroxy-2-(4-methoxy-2-methylphenyl)-1,2,5,10tetrahydropyridazino-[4,5b]quinoline-1,10-dione sodium

as will be discussed below.Introduction Although quinolinic acid (2. This situation changed when quinolinic acid was shown to activate selectively the population of glutamate receptors that are also sensitive to N-methyl-D-aspartate (NMDA) [2]. although the mechanism was unknown. thus.3-pyridine-dicarboxylic acid) was recognised as a metabolite of tryptophan for many years. After exploring the potential neuro-activity of other tryptophan metabolites along the same pathway (kynurenines) it was later found that kynurenic acid was an antagonist at NMDA receptors. nicotinamide and the ubiquitous enzyme co-factor nicotinamide adenine dinucleotide (NAD). it was thought to be merely an inactive precursor in the synthesis of nicotinic acid and. raising the possibility of a role in several forms of accidental or disease-related brain injury [4-6]. Several families of glutamate receptor blockers for potential therapeutic use were designed based on the structure of kynurenic acid [8-10]. It was known that direct administration of high concentrations into the brain could induce convulsions [1]. receptors which were soon thereafter to be implicated in synaptic transmission and neuronal plasticity phenomena such as long-term potentiation and long-term depression. This discovery led to the direct demonstration that over-activation of NMDA receptors by quinolinic acid could produce neuronal degeneration in the brain [3]. . with a lesser ability to block other glutamate receptors responding to kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) [7].

and potentiate. This possibility is strengthened by data showing a potentiation of quinolinic acid neurotoxicity by the pro-inflammatory cytokine interleukin-1β (IL-1β) [15]. . and increase cell death produced by quinolinic acid or other NMDA receptor agonists. compounds which have been shown to be neuroprotective against injurious stimuli and chemical insults in a variety of conditions [19].Excitotoxicity Although quinolinic acid can produce damage by its activation of NMDA receptors [3. at least partly by potentiating amino acid-induced calcium influx [16]. This might therefore be consistent with a role for quinolinic acid in neurotoxicity induced by inflammatory stimuli or a range of alternative triggers such as the dopaminergic toxin 1-methyl-phenylpyridinium (MPP+) and the glutamate receptor agonist kainic acid. the toxicity of this combination can be prevented by antagonists at the A2A receptors for adenosine. The kynurenine pathway and quinolinic acid generation are activated by pro-inflammatory factors. Indeed these molecular species may contribute to. and this interaction may be relevant to the notion that inflammation triggered within the central nervous system (CNS) may contribute to the development of neurodegenerative disorders such as Alzheimer's disease and Huntington's disease.11] it can also induce. since there is some evidence that IL-1β can inhibit excitotoxic neuronal damage [17] and a deficiency may increase neuronal injury [18]. Interestingly. Some of these differences may be attributable to the use of different experimental models and cytokine concentrations. a controversial area. This is. which has itself been implicated in the damaging effects of stroke. superoxide and hydroxyl radicals [12. or facilitate the production of. The cytokine may produce neurodegeneration itself. however. reactive oxygen species such as hydrogen peroxide.13]. the neurotoxic effects of quinolinic acid in vivo [14].

quinolinic acid can attain potentially toxic levels in the blood or cerebrospinal fluid (CSF) following cerebral insults such as trauma. since quinolinic acid is generated in the same types of immune-competent cells that can generate IL-1β [20.21]. The relationship between quinolinic acid and neurodegenerative disorders has attracted a great deal of interest. are much lower than the millimolar levels often required to induce neuronal damage. the levels of compounds in body fluids represent substantial dilutions from their cellular sites of origin and release. ischaemia [11. which are usually less than 50nM. their combined presence at higher levels could further enhance local toxicity. 22. levels only slightly higher than the resting levels of approximately 10-50nM. and the local concentrations of quinolinic acid may be many times greater in the extracellular space around those activated glial cells and macrophages which produce it. there may be subsets of neurons which are particularly sensitive to quinolinic acid toxicity. These possibilities are entirely consistent with the increasing evidence that microglial activation makes a substantial contribution to various form of brain damage. Special interest has developed into a possible role in Huntington's disease in the light of molecular studies in yeast models [25] and a strong association between activity along the kynurenine pathway and the length of the CAG triplet nucleotide repeat sequence in patients at different stages of the . In addition. However.A commonly voiced concern about the possible role of quinolinic acid in neuronal damage is that its concentrations in the blood and cerebrospinal fluid (CSF). Some cells can be killed by maintained exposure to concentrations of around 100nM quinolinic acid. Indeed. Finally. 23] or microbial infections [24]. even after its dilution from its sites of generation.

kynurenic acid blocked the effects of exogenously applied acetylcholine or α7-nicotinic receptor-selective agonists [29]. 27]. 11. The ability of kynurenic acid to block nicotinic synaptic transmission may be important to kynurenic acid pharmacology in the hippocampus.disorder [26]. glutamate-mediated epsps. Subsequent work revealed that kynurenic acid could block that component of excitatory post-synaptic potentials (epsps) mediated by the activation of cholinergic. This link between neurotoxicity and neurodegeneration is addressed in other chapters in this issue.epsps also blocked by methyl-lycaconitine. an established antagonist at the α7 receptor. kynurenic acid [10. Dihydro-βerythroidine. In studies of cultured neurons as well as brain slices. which blocks α4β2 receptors. Other kynurenines. Although the emphasis to date in the understanding of neurodegeneration has been focussed on quinolinic acid. confirming the importance of the α7 receptors. Kynurenic acid is recognised largely for its ability to block glutamate receptors. Kynurenic acid reduced the amplitude of these epsps with an EC50 of 136 μM and was more potent in blocking the nicotinic epsps than the full. was ineffective. this compound represents only one component of the kynurenine pathway of tryptophan oxidation (Figure 1)[10. nicotinic α7 receptors in hippocampal interneurons [30] . especially the NMDAR at which it blocks the actions of the co-agonist glycine. although it is less potent than when used to block exogenously applied . The pathway also generates a glutamate antagonist. 28] and highly redoxactive compounds such as 3-hydroxykynurenine and 3-hydroxyanthranilic acid.

although much less is known about its selectivity and activity. In fact. kynurenic acid can be formed by the nonenzymic oxidation of kynurenine and tryptophan via indole-3-pyruvic acid [34]. A possible relationship between the levels of kynurenic acid and patient mortality has been noted by several groups [32. KAT exists in two major forms. 1) activity increases with age. The difference in potency could also be a result of the different state of differentiation of cells in culture. KAT I being primarily cytosolic in location. the relative absence of glial cells or the different relationships between synaptic terminals and glia with their complement of enzymes and transporters. 33]. and this can inhibit superoxide dismutase. in addition to its formation by kynurenine aminotransferase (KAT). The levels in blood increased significantly in a sub-population of patients who died within 21 days of a stroke compared with patients who survived for a longer period [31]. kynureninase and kynurenine-3-monoxygenase are at least partly dependent on the availability of vitamin B6 (pyridoxine. A third form of KAT has been identified. . Increased levels of nitric oxide have been noted after brain injury. and KAT II being primarily mitochondrial. a reaction which is increased by oxidative stress. PLP) for their activity. since KAT. Fig.cholinomimetics in culture. The resulting increase in superoxide anions could oxidise indolepyruvate to kynurenic acid. consistent with reports that nitric oxide donors increase kynurenic acid production [35]. The latter is identical to α-aminoadipate aminotransferase. There is some influence of diet and nutritional status on this and other kynurenine pathway enzymes.3-dioxygenase (IDO. One reason for such a relationship may lie in the fact that. Several clinical studies have examined the levels of kynurenic acid in patient groups. possibly analogous to reports that indoleamine-2.

3hydroxyanthranilic acid can auto-oxidise to quinoneimines. blood samples were taken from patients as soon as possible after entering hospital in the immediate aftermath of a stroke and for up to 14 days thereafter [31]. the existence of brain damage was indicated by an early increase in the levels of protein S100B. The balance of this redox cycling behaviour will depend on local concentrations of iron and copper. Neopterin levels. In a recent study on humans. but the reaction products can then oxidise other molecules [37. There was also a highly significant decrease in the ratio of 3-hydroxyanthranilic acid: anthranilic acid which was strongly correlated with infarct volume indicated in computed tomography brain scans [31]. Some of the kynurenine compounds are of increasing interest in disorders of brain function. although this persisted for several days.3-dioxygenase [TDO]. the levels and activities of other free radical generators and anti-oxidants. which influences both redox activity and metal ion availability [39]. Under physiological conditions. and pH.3-hydroxyanthranilic acid can generate reactive oxygen species such as hydrogen peroxide and superoxide when in the presence of transition metal ions but it is also a highly efficient scavenger of free radicals [36]. As expected from earlier work by others. 38]. perhaps reflecting the progressive development of delayed neuronal damage. since blood levels of kynurenine and tryptophan revealed an increased kynurenine: tryptophan ratio consistent with activation of the initial enzymes of the pathway – [IDO] and tryptophan-2. together with activation of the kynurenine pathway. a well-established marker of inflammation [41] were also substantially elevated. The experimental evidence for a role of kynurenines in stroke injuries is firmly based on the demonstration that inhibition of the pathway reduces the neuronal damage which follows cerebral vessel occlusion in rodents [40]. .

including the activation of microglia which are thought to contribute to brain damage following stroke. though the reciprocal changes suggests a biochemical connection such as the conversion of anthranilic acid (AA) into 3-hydroxyanthranilic acid (3HAA) [42]. It can also suppress the responses of T cells to allogeneic stimuli [45]. observed now in several disorders including osteoporosis. Huntington’s disease. chronic brain injury. The loss of 3HAA may have important consequences for the immune system. would seem to be protective. kynurenic acid. limiting the inflammatory response. The overall result of the changed 3HAA:AA ratio. Anthranilic acid interacts with copper to form an anti-inflammatory complex able to remove highly injurious reactive oxygen species [48. acting primarily on Th1 rather than Th2 cells [46]. This interest is . stroke and depression [43] could then indicate that inflammation generates a decrease in that conversion.The reason for the changed ratio is not clear. The changed ratio. Several anthranilic acid derivatives have similar. marked anti-inflammatory activity [50] and it is an intriguing possibility that the high levels of anthranilic acid in some disorders such as strokes might be converted to anti-inflammatory compounds as a mechanism to reduce tissue damage. and decreases the ability of dendritic cells to activate T cells [47]. therefore. 3hydroxyanthranilic acid inhibits the proliferation of CD8+ T cells [44]. The kynurenine pathway as a pharmacological target Interest in the kynurenine pathway as a potential site of drug action has centred around the possibility of modifying the balance between the endogenous concentrations of quinolinic acid and it’s antagonist. thoracic disease. coronary heart disease.49].

These secondary processes may be classified generally as inflammatory. not by the initial insult itself. This hypothesis has received much support in principle from the discovery that the spinal degenerative disorder amyotrophic lateral sclerosis. Huntington's disease and Parkinson's disease respectively. or motoneurone disease. since there is growing evidence that they are mediated by cytokines and chemokines produced by glial cells that are immunologically activated by products of the initial insult. especially NMDA receptors. 52] and stroke [31].expanding in view of the wide range of clinical disorders in which abnormalities in the pathway have been proposed. The resulting accumulation of extracellular glutamate generates oxidative stress that ultimately leads to the demise of the motoneurones. a loss of transporters or increased presence of receptors for glutamate in localised regions of the brain such as the nucleus basalis. One of the popular hypotheses for the aetiology of disorders such as Alzheimer's disease. seems to be the enhancement of neuronal damage to some extent (as noted above). however. One consequence of this central inflammatory response. neostriatum or substantia nigra could cause or contribute to the neuronal death in Alzheimer's disease. These compounds play a key role in attracting and modulating the activity of peripheral monocytes and macrophages that invade the CNS and participate in the removal of damaged tissue and the control of potential infections. but by secondary processes entrained by that insult. It is probable also that much of the chronic brain damage occurring after stroke injury is the result of ‘delayed neurodegeneration’ which is caused. By analogy. but with probably the greatest interest in the neurodegenerative disorders. including AIDS-related dementia [51. Parkinson's disease and Huntington's disease is that there is an ongoing overactivation of glutamate receptors. is the result of a defective glutamate transporter. The activation of immune- .

This protection was associated . [54] could prevent death and ataxia in mice infected with the malaria parasite Plasmodium [55]. Septicaemia is similarly associated with increased serum and CSF quinolinic acid (10-fold in serum and 30-fold in CSF) and kynurenine. 1) which reduces the production of quinolinic acid [53].competent cells – peripheral macrophages or central microglia – also includes induction of the kynurenine pathway. changes which correlate well with markers of immune activation such as neopterin [52]. There are substantially elevated levels of quinolinic acid in the brains of children with bacterial infections of the CNS. More recently.4-dimethoxy-N-[4-(3-nitrophenyl)-thiazol-2-yl]-benzenesulfonamide (Ro61-8048) described by Roever et al. Infection of mice by Herpes simplex virus type 1 raised the levels of quinolinic acid in mice. an inhibitor of kynurenine-3-monoxygenase (KMO. attention has focussed on parasitic infections. This view is supported by the demonstration that the excitotoxic response to kainic acid – a response generally attributed almost exclusively to the direct activation of kainate receptors and the consequent calcium influx – can be reduced significantly by the co-administration of m-nitrobenzoylalanine. with reports that the KMO inhibitor 3. Infections of the CNS. Fig. By activating IDO. The implication is that the secondary activation of microglia includes the generation of increased levels of quinolinic acid or other kynurenines (see below) that exacerbate neuronal damage. in parallel with paralysis. so that quinolinic acid will also be generated and could contribute to the ‘inflammatory’ response and the later phases of damage (known as ‘delayed degeneration’). viral components or bacterial lipopolysaccharides increase the production of several kynurenines.

Ischaemic damage. as a result. Central microglia and macrophages may contribute to delayed neuronal death after cerebral ischaemia [58] since they possess and secrete quinolinic acid as noted above and as reflected in the existence of quinolinic acidpositive microglia in the brain following transient global ischaemia [59]. a delayed increase of quinolinic acid was noted in gerbils subjected to a period of cerebral ischaemia. with a significant reduction by Ro61-8048 of the later stages of brain pathology occurring in mice infected with Trypanosoma brucei parasites [56]. Huntington's disease The injection or infusion of quinolinic acid into the rodent striatum has become a widely accepted paradigm for generating electrophysiological. Intracisternally applied tryptophan was converted to quinolinic acid in damaged but not normal areas of brain.with the predictably raised levels of kynurenic acid. In addition to the work on stroke introduced above. There was no change of kynurenine aminotransferase activity and. A similar protection has now been demonstrated in trypanosomiasis (sleeping sickness). neuropathological and behavioural changes closely resembling those seen in patients with Huntington's . consistent with a local production at the sites of injury. with quinolinic acid levels rising to 50-fold their basal value after 7 days [57]. There was an accompanying increase in the activity of several of the kynurenine pathway enzymes in those brain regions experiencing an interrupted blood supply. there was an increased ratio of quinolinic acid: kynurenic acid which would tend to exacerbate the degree of neuronal injury. and also of anthranilic acid and the chemotactic monocyte chemoattractant protein-1.

there is a real possibility that interference with the pathway could slow or prevent the development of symptoms or the progression of the disorder. When considered together with the clinical evidence for parallel changes in the CAG triplet repeat sequence. The most obvious way to base a therapeutic strategy for neuroprotection on the kynurenine pathway is to mimic the glutamate blocking activity of kynurenic acid. several approaches . Even in non-human primates quinolinic acid is able to induce motor disabilities very similar to the involuntary movements of Huntington’s disease [62. since over-activation of the various glutamate receptors may be a key characteristic of brain damage in stroke or neurodegeneration. including neuronal vacuolisation or disturbing psychotomimetic effects. with the beneficial corollary that kynurenic acid analogues generally cross the blood–brain barrier more easily than many of the glutamate site quinoxaline ligands. particularly symptoms which develop in the early stages of the disorder [61]. These problems contributed to a shift in emphasis towards the glycine-B co-agonist site on the NMDA receptor. A therapeutic strategy Kynurenic acid analogues A major effort to develop antagonists acting directly at the glutamate binding sites resulted in a large number of compounds with therapeutic promise. To this end. with the resulting increase of kynurenic acid levels and possible lowering of quinolinic acid production. 63].disease [60]. represents a promising avenue for this therapeutic approach. symptoms. and kynurenine metabolism [26]. although some exhibited neurotoxic and psychological side effects. Inhibition of KMO.

although oral bioavailability was reduced. 68] (Fig. were bioavailable after oral administration [66]. Such additions have led to amido.6-dichloro-2-carboxyindole-3-yl)propionic acid) [67. and was an effective anticonvulsant in mice.7-dichlorokynurenic acid with an IC50 of only 80 nM as an antagonist at the glycine-B site on the NMDA receptor. 2) has been used extensively to displace compounds at the strychnine-resistant (NMDA-linked) glycine binding site. The potency of these compounds is increased further if the 4-hydroxy group of kynurenic acid is substituted by acetic acid or similar moieties.560 binding. Kynurenic acid has also been converted into 2-quinolone sulphonamide analogues with good antagonistic potency. The presence of a 3-keto grouping was retained in quinones such as L701.7-dichloro-4-[[(Nphenylamino)-carbonyl]amino]-1.7-dichloroquinoline-2-carboxylic acid) [64.560 (2-carboxy-5. presumably partly as a result of this property. 65] (Fig. Lipid solubility and blood– . 2) which showed nanomolar potency at displacing L689.951 (3-(4.3.have been reported in which the kynurenic acid molecule itself is modified by the addition of halogen atoms. A breakthrough in kynurenic acid pharmacology arrived with the demonstration that the quinoline nucleus could be replaced by the indole nucleus with a retention of glutamate antagonism.748 (4-[(carboxymethyl)amino]-5. while L689. This can generate potent antagonistic analogues such as 5.252 (4-hydroxy-3(cyclopropylcarbonyl)-7-chloroquinoline-2(1H)-one) (Fig. 2). 2)proved to be highly effective. Of many subsequent analogues of this structure MDL29. A valuable discovery was made when it was found that 3-phenyl substituents retained potent activity at the NMDA/glycine site but they were also more lipophilic than earlier compounds and.2. Some of these compounds have shown clear therapeutic potential as neuroprotectants or anticonvulsants.4-tetrahydroquinoline) (Fig.and thio-substituted compounds such as MDL 100.

The B ring of the kynurenate nucleus is also amenable to modification by a range of substituents. as in L701. esterified 4-amino analogues are converted into kynurenic acid in the brain. Similarly. Replacement of the nitrogenous ring of kynurenate by a seven-membered ring to yield benzazepinedione compounds allows retention of antagonism at NMDA receptors.5. 2) [69]. with .324 (4-hydroxy-7-chloro-3-(3phenyloxy)phenyl-quinoline-2(1H)-one (Fig. Esterified analogues of kynurenic acid penetrate into the CNS significantly more rapidly than kynurenic acid itself. Once within the brain parenchyma. was able to protect the brain up to at least 24 hours after middle cerebral artery occlusion [70]. such compounds can be converted to kynurenic acid itself. protection against cerebral ischaemia and the ability to displace strychnine-resistant glycine binding in vitro or ex vivo [71]. Both this compound and a sulphur-containing analogue have good antagonistic activity at the glycine-B coagonist site and acceptable systemic and oral bioavailability.5b]quinoline-1.10-dione sodium) (Fig. leading to greater persistence of compounds in the brain may account for the efficacy of the Zeneca compound ZD9379 (7-chloro-4-hydroxy-2-(4methoxy-2-methylphenyl)-1.brain barrier penetration are increased if the 3-position of the kynurenate nucleus is occupied by highly lipophilic substituents.10-tetrahydropyridazino-[4. with a half-life of 34 hours in rats. 2) which. A long half-life. Neuronal damage produced by focal cerebral ischaemia can be reduced by a number of compounds in rats. Pro-drugs The use of pro-drugs to deliver kynurenic acid or its analogues directly into the brain provides an alternative approach to overcoming the limitations of the bloodbrain barrier.2. even when administered several hours after the insult.

The ratio of quinolinic acid: kynurenic acid is largely determined by KMO (Fig. 1) and a number of investigators have attempted to define the molecular features of molecules required to achieve inhibition of this enzyme without having non-specific effects on related flavine mono-oxygenases. 73]. The feasibility of this approach was first demonstrated by the development of nicotinylalanine as an inhibitor of kynureninase and KMO [74-76] (Fig. while precursor analogues such as L4-chloro-kynurenine and 4. .retention or increase in their functional activity. 1).6-dichlorokynurenine are metabolised to the highly potent kynurenic acid derivatives 7-chlorokynurenic acid and 5. The change in the ratio of quinolinic acid: kynurenic acid was assumed to underlie the anticonvulsant and neuroprotective properties of nicotinylalanine. Enzyme inhibitors A different approach is to interfere with the enzymes of the kynurenine pathway so as to modify the ratio between quinolinic acid and kynurenic acid levels. These neurochemical changes were substantially greater when nicotinylalanine was administered together with kynurenine and the acidic transport inhibitor probenecid. or to alter the relative concentrations of other components of the pathway. The Inhibition of KMO reduced the levels of endogenous quinolinic acid but increased the conversion of kynurenine to kynurenic acid.7-dichlorokynurenic acid [72. which limits the efflux of kynurenic acid formed within the brain. A similar shift of balance should be attainable by inhibiting kynureninase.

The compound used almost exclusively at the present time to inhibit KMO is one of a series of N-(4-phenylthiazol-2-yl) benzenesulphonamides. while orthomethoxybenzoylalanine preferentially inhibits kynureninase [ 77. Concentrations of both metabolites were increased substantially in the rat hippocampus after a single systemic injection and. 3) inhibits KMO with an IC50 of only 37 nM. FCE28833A (3.4-dichlorobenzoylalanine) (Fig. Ro618048 (Fig. The former produces higher levels of kynurenine and kynurenic acid in the brain and peripheral tissues. the levels of kynurenic acid remained high for 24 h after the injection [80]. . A second approach to preventing the synthesis of quinolinic acid is to inhibit 3hydroxyanthranilic acid 3. This probably accounts for the decrease of locomotion and suppression of seizures in sensitive strains of mice [79]. 78]. 3) is active after systemic administration and inhibits KMO more effectively than meta-nitrobenzoylalanine leading to an increase of kynurenine and kynurenic acid in the brain. It also increased the levels of kynurenic acid in the extracellular fluid of gerbil brain after oral administration [54].Related compounds developed since this initial proof of concept work generated meta-nitrobenzoylalanine which preferentially inhibits KMO. This compound. 82]. Good inhibition is produced by a series of 4-halo-3-hydroxyanthranilic acids which produce a corresponding reduction in the formation of quinolinic acid [81. interestingly from a therapeutic viewpoint.4-dioxygenase. The inhibition of KMO produced the expected fall in 3-hydroxykynurenine levels together with the increase of kynurenic acid. but both have been shown to increase the amount of kynurenic acid in the hippocampus in vivo.

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.Figure 1 Diagrammatic summary of the major component compounds and enzymes of the kynurenine pathway for the oxidation of tryptophan.

including the compounds quinolinic acid and kynurenic acid which are of primary relevance to the text. .Sequence of steps in the pathway from tryptophan to nicotinic acid and NAD.

Figure 2 Chemical structures of compounds discussed .

. Most act at the glycine-B receptor site on the NMDA receptor.The structures are shown of several of the glutamate receptor blocking compounds based on the structure of kynurenic acid. the preferred site of action of kynurenic acid.

Figure 3 Chemical structures of compounds discussed. The structures are shown of the two main inhibitors of the kynurenine pathway that are neuroprotective and prevent excitoxicity by blocking kynureninase or kynurenine3-monoxygenase (KMO). .