Development and therapeutic potential of kynurenic acid and kynurenine derivatives for neuroprotection

REVIEW

Development and therapeutic potential of kynurenic acid and kynurenine derivatives for neuroprotection Trevor W. Stone Manipulation of the kynurenine pathway of tryptophan metabolism has yielded a plethora of agents that are now being developed as neuroprotectants and anticonvulsants. This pathway is involved in the production of the excitotoxin quinolinic acid and the neuroprotectant kynurenic acid. Approaches used in the development of therapeutic agents include production of analogues or pro-drugs of kynurenic acid and inhibitors of the enzyme responsible for the synthesis of quinolinic acid. Indeed, analogues of the amino acid receptor antagonist kynurenic acid are now in, or are about to enter, clinical trials for stroke and related disorders. This review summarizes the mechanism of action of these various agents, the development of glutamate receptor antagonists from kynurenic acid and the range of their potential uses in neurology and psychiatry. The neuronal damage that characterizes neurodegenerative disorders such as Alzheimer’s disease or Parkinson’s disease, and which follows such cerebral insults as stroke or traumatic injury, cannot be prevented by currently available drugs. The brain damage is believed to result, in part, from over-activation of glutamate receptors, which leads to a rise of intracellular Ca21 that promotes cell damage by both activating destructive enzymes and increasing the formation of reactive oxygen species1. Interest has centred on the NMDA-sensitive subtype of glutamate receptors because these receptors allow a greater rise of intracellular Ca21. However, despite the development of some very selective NMDA receptor antagonists, such as the non-competitive channel blocker dizocilpine (MK801) and the competitive antagonist selfotel, NMDA receptor antagonists exhibit disappointing efficacy in clinical trials and have produced neuronal vacuolization and psychotomimetic effects. Kynurenic acid and quinolinic acid

The kynurenines are metabolites of tryptophan2 (Fig. 1); interest in their importance to neurobiology was aroused with the discovery that two components of the pathway acted on glutamate receptors. Quinolinic acid was shown to excite neurones via the activation of NMDA receptors3, and consequently produced neuronal damage4, whereas kynurenic acid proved to be an antagonist at NMDA, kainate and AMPA receptors5. Kynurenic acid can block glutamate receptors in rodents5 and primates6 and can distinguish subpopulations of kainate receptors7. In addition, there is evidence for an additional, novel site of action of kynurenic acid2. Several years after the realization that kynurenic acid was an antagonist at all subtypes of glutamate receptor5 it was found to be particularly active as an antagonist at an allosteric site on the NMDA receptor8 for which glycine or D-serine might be endogenous, essential co-agonists. Other kynurenines

The kynurenine pathway includes at least two other compounds relevant to neurodegeneration; 3-hydroxykynurenine

and 3-hydroxyanthranilic acid can both produce neuronal damage, although primarily by the induction of free radical formation rather than an action on glutamate receptors9. Similarly, neuronal damage induced by quinolinic acid is also partly attributable to oxidative stress10. Therapeutic approaches based on the kynurenine pathway

In an attempt to develop therapies for the treatment of neurodegeneration and epilepsy, the kynurenine pathway has been manipulated in several ways. The original approach involved the use of analogues of kynurenic acid as antagonists at glutamate receptors. A second approach uses pro-drugs of kynurenic acid or its analogues, which can be hydrolysed within the CNS, whereas a third, and the most recent approach, is inhibition of the activity of the enzymes responsible for synthesizing the NMDA receptor agonist quinolinic acid. This diverts kynurenine metabolism away from the production of the excitotoxin and towards the production of the amino acid antagonist kynurenic acid. Kynurenic acid derivatives as glutamate receptor antagonists

The first attempts to improve on the biological activity of kynurenic acid (Fig. 2) involved substitution with halogen atoms yielding, for example, 5,7-dichlorokynurenic acid11, which has an IC50 of 80 nM against strychnine-resistant glycine binding. The 7-chloro or 5,7-dichloro formulae have been retained in many analogues developed subsequently. Replacement of the 4-hydroxy group of kynurenic acid with acetic acid or similar substituents further increased potency and led to the development of amido- and thiosubstituents in the 4-position and potent analogues such as MDL100748 (Ref. 12) and L689560 (Ref. 13) (Fig. 2). Audiogenic seizures in susceptible mice can be prevented by MDL100748 with an ED50 of 83 mg kg21 after systemic injection. L689560 has become a standard with which subsequent analogues have been compared; the displacement of [3H]L689560 has often been used as an alternative assay to that of displacing [3H]glycine.

0165-6147/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0165-6147(00)01451-6

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T.W. Stone, Professor of Pharmacology, Institute of Biomedical and Life Sciences, West Medical Building, University of Glasgow, Glasgow, UK G12 8QQ. E-mail: T.W.Stone@ bio.gla.ac.uk

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CH2CHCO2H NH2 N

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Nicotinamide acid dinucleotide (NAD) trends in Pharmacological Sciences

Fig. 1. The major components of the kynurenine pathway that possess neurobiological activity are shown. The pathway, which accounts for the majority of non-protein tryptophan metabolism in most tissues, includes quinolinic acid (an agonist at NMDA receptors2,3), 3-hydroxykynurenine (a radical-generating neurotoxin9) and kynurenic acid (a glutamate receptor antagonist with differences in potency at the various receptor subtypes2,5). The conversion of tryptophan to kynurenine is catalysed by tryptophan-2,3-dioxygenase in the liver and by the less selective indoleamine-2,3-dioxygenase in most other tissues. In most cases, this is the rate-limiting step in the pathway.

Kynurenate analogues such as MDL104653 (Fig. 2), with a 3-phenyl substituent, retained potent activity at the NMDA receptor glycine site but exhibited better lipid solubility and oral bioavailability14. The retention of a keto grouping at position 3 yielded quinones such as L701252, which has an IC50 of 420 nM against L689560 binding and an ED50 of 4.1 mg kg21 against seizures in DBA/2 mice. Among the 2-quinolone series, a group of sulfonamide analogues of kynurenic acid are also active. Of a series of 3,4-dihydroquinolones and tetrahydroquinolines, those with a nitrosubstituent in the 3-position were selective antagonists at the NMDA receptor glycine site provided they bore a bulky grouping at position 4. The compound with no substitution at position 4 (3-nitro-7-chloro-3,4-dihydroquinoline-2-one; Fig. 2) proved to be one of the most effective broad-spectrum antagonists of NMDA and AMPA receptors known at the time15. Kynurenic acid analogues in which the six-membered nitrogen-containing ring was replaced by a five-carbon ring were also active. The simplest of these indole analogues included SC49648 (Ref. 16) but one of the most effective was MDL29951 (Ref. 12), an agent with an IC50 of 140 nM against glycine binding and 2500 times less activity at the glutamate binding site. However, this compound has poor bioavailability and doses of up to 400 mg kg21 were required to suppress audiogenic seizures. Expansions of the substituent at the 3-position led to compounds such as GV150526A (Ref. 17) (Fig. 2). Heterocyclic substitutions have been incorporated into the kynurenic acid nucleus or incorporated into its sidechains. This strategy has yielded compounds with potential clinical value such as RPR104632 (Ref. 18) and ZD9379 (Ref. 19). The most recent modifications of kynurenic acid have included attempts to improve the lipid solubility and blood– brain barrier penetration of compounds by including lipophilic substituents in the 3-position of the kynurenic acid nucleus (L701324)20 or its indole-based derivatives21. The two compounds L701324 and the sulfur-containing analogue L705022 are among the most promising kynurenic-acid-derived glycine site antagonists developed to date, with high activity at the

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glycine site in vitro, and comparable activity at suppressing seizures and neurotoxicity in vivo after either systemic or oral administration. Glutamate receptor antagonism is retained in compounds in which the B-ring of kynurenic acid is replaced by a substituted five-membered ring. Alternatively, enlargement of the nitrogenous ring of kynurenic acid into a seven-membered ring has produced benzazepinedione compounds such as 8-chloro-3-hydroxybenzazepin-2,3-dione (Fig. 2) with activity at NMDA receptors. This compound displaces strychnineresistant glycine binding with an IC50 of 30 nM and blocks amino acid receptors in vivo after intravenous administration of 600 mg kg21 (Ref. 22). In addition, it reduces seizures in DBA/2 mice at an ED50 dose of 13 mg kg21, and when infused at 5mg kg21 h21 for 8 h, it induced a 33% reduction of ischaemic brain damage. Analogues with 3-aryl substituents are less potent but possess good CNS bioavailability22. Pro-drugs of kynurenic acid and its analogues

Esters of kynurenic acid and its analogues penetrate the CNS more readily than the parent compounds, but are hydrolysed back to the analogues within the brain. Similarly, 2-carboxyethyl-4-methylamino-5,7-dichloroquinoline (Fig. 2) is hydrolysed within the CNS to an active 4-amino analogue of kynurenic acid. L-4-Chloro-kynurenine is transported into the brain where it is converted by kynurenine aminotransferase into 7-chlorokynurenic acid, whereas 4,6-dichlorokynurenine is taken into brain and converted to 5,7-dichlorokynurenic acid23. Rao et al.16 developed analogues that penetrate easily into the brain where they are hydrolysed to the active substance SC49468 (Fig. 2). Modulators of quinolinic acid and kynurenic acid concentrations

Because quinolinic acid is an agonist at NMDA receptors and kynurenic acid is an antagonist at this receptor, together with the fact that 3-hydroxykynurenine is neurotoxic9, an alternative approach to modifying glutamate receptor function and affording neuroprotection is to decrease the formation of quinolinic acid and 3-hydroxykynurenine, and to increase the levels of kynurenic acid. It has been suggested that this

REVIEW O

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8-Chloro-3-hydroxy- 2-Carboxyethyl-4-methylamino5,7-dichloroquinoline benzazepin-2,3-dione trends in Pharmacological Sciences

Fig. 2. Stuctures of analogues of kynurenic acid used as antagonists at the glycine site of the NMDA receptor complex.

strategy might not be beneficial because of the low potency of quinolinic acid as a receptor agonist, and the presence of low concentrations of kynurenines in the CNS. However, quinolinic acid is more potent as a neurotoxin than as a neuronal excitant, possibly because it enhances free radical formation10, and much higher concentrations can be attained locally in the extracellular space than are indicated by gross extracellular measurements. This is particularly likely when an inflammatory reaction occurs following brain injury or degeneration because glia and activated cells of the immune system (some of which can penetrate into the CNS) can produce large amounts of quinolinic acid24,25. During CNS inflammation, the levels of quinolinic acid can rise several-100-fold26, and quinolinic acid is increasingly regarded as a significant contributor to AIDS-related dementia27. Inhibition of kynurenine-3-hydroxylase (Fig. 1) results in a decrease in the concentration of endogenous quinolinic acid and an increase in the concentration of kynurenic acid. The change in the balance of this pathway away from the excitotoxin and towards the neuroprotectant is predicted to have anticonvulsant and neuroprotective properties in stroke and epilepsy.

The practicality of this approach was demonstrated by the development of nicotinylalanine (Fig. 3) as an inhibitor of this enzyme28,29. Administration of nicotinylalanine with L-kynurenine and probenecid increased the brain concentration of kynurenic acid and prevented the induction of seizures28–31. Of a series of related compounds, m-nitrobenzoylalanine (Fig. 3) preferentially inhibits kynurenine-3hydroxylase with an IC50 of 900 nM, whereas o-methoxybenzoylalanine preferentially inhibits kynureninase (Fig. 1)32. Although m-nitrobenzoylalanine is more potent at increasing kynurenine and kynurenic acid levels, both m-nitrobenzoylalanine and o-methoxybenzoylalanine can increase the amount of kynurenic acid in the hippocampus in vivo, an effect that is associated with a decrease in locomotion and a suppression of seizures33. The inhibition of kynurenine-3-hydroxylase by m-nitrobenzoylalanine also causes a decline in the concentration of 3-hydroxykynurenine (Fig. 1), whereas o-methoxybenzoylalanine increases the concentration of 3-hydroxykynurenine in the brain but does not reduce the concentration of brain 3-hydroxyanthranilic acid. This paradox might result from the fact that an alternative pathway exists from kynurenine,

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trends in Pharmacological Sciences

Fig. 3. Structures of compounds that can inhibit kynureninase or kynurenine3-hydroxylase.

via anthranilic acid, to 3-hydroxyanthranilic acid. Although this pathway is catalysed by kynureninase, it is possible that different isoforms of this enzyme are involved, or that the balance between the two routes is changed by o-methoxybenzoylalanine. Therefore, the administration of kynurenine-3-hydroxylase inhibitors is the most rational way to elevate brain concentrations of kynurenic acid and decrease the amount of 3hydroxykynurenine and quinolinic acid in the brain simultaneously34. A related kynurenine-3-hydroxylase inhibitor PNU156561 (formerly FCE28833A) (Fig. 3) induced peak increases of ten- and 80-fold in the resting concentration of kynurenine and kynurenic acid, respectively, in hippocampal dialysates following a single systemic injection; these concentrations remained elevated for 22 h (Ref. 35). A series of N-(4-phenylthiazol-2-yl) benzenesulfonamides are potent inhibitors of kynurenine-3-hydroxylase. One member of this series, Ro618048 (Fig. 3) has an IC50 of only 37 nM and is effective after oral administration in gerbils36, with doses of 100 mmol kg21 raising the concentration of brain kynurenic acid 7.5-fold. In models of cerebral ischaemia, Ro618048 reduced rat hippocampal neuronal loss from 92% to 10% after three doses of 40 mg kg21; m-nitrobenzoylalanine was also effective37. Ro618048 is particularly effective when the immune system is activated, because this leads to an induction of tryptophan-3,4-dioxygenase activity and an increase in kynurenine biosynthesis both peripherally and in the brain; kynurenine-3-hydroxylase inhibitors can then suppress quinolinic acid formation significantly38. In experimental allergic encephalitis, a model of multiple sclerosis, brain concen-

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trations of quinolinic acid are raised 60-fold above normal, but Ro618048 can reduce this increase by 85% (Ref. 39). S-Aryl-L-cysteine-S,S-dioxides have also been developed as potent inhibitors of kynureninase. These compounds have been shown to reduce the stimulation of quinolinic acid synthesis induced by interferon g in human macrophages. Similarly, 7-chloro-3-methyl-1H-pyrrolo[3,2-c]quinoline4-carboxylic acid has an IC50 of 8.1 mM against the rat brain kynureninase40 but inhibits kynurenine aminotransferase by only 24% at 100 mM. A series of 4-phenyl-4-oxobutanoic acid analogues and phosphinic acid and methylphosphinate analogues of kynurenine can also inhibit this enzyme41. One of the outstanding debates in the kynurenine field is whether manipulation of the pathway can modify the levels of quinolinic acid or kynurenic acid sufficiently to be neuroprotective. In general, the concentration of kynurenic acid required to block glutamate receptors lies in the range 10–1000 mM, although the maximum levels reached in the brain are less than 1 mM. However, it is becoming clear that small elevations of kynurenic acid in vivo can have a disproportionate effect on neuronal function and viability. This might, in part, reflect actions that are not yet fully appreciated, such as the ability of nanomolar concentrations of kynurenic acid to suppress glutamate release following the administration of m-nitrobenzoylalanine42, or the fact that local concentrations of endogenously produced kynurenic acid can reach much higher levels than those of externally administered kynurenic acid43. Perhaps the most obvious method to lower the concentration of quinolinic acid is to inhibit the initial enzyme tryptophan-3,4-dioxygenase. An inhibitor of tryptophan dioxygenase, 540C91, prevents the elevation of quinolinic acid caused by tryptophan loading44. Such a drug should be useful when dioxygenase activity is induced by inflammation. A further means to prevent the synthesis of quinolinic acid is to inhibit 3-hydroxyanthranilic acid 3,4-dioxygenase. 4-halo-3-hydroxyanthranilic acids inhibit this enzyme and suppress quinolinic acid formation45. Most recently, NCR631 has been developed by AstraZeneca; this compound inhibits 3-hydroxyanthranilic acid oxygenase and reduces the loss of hippocampal cells produced by anoxia or injurious cytokines46. Therapeutic indications and trials of kynurenic acid analogues Cerebral ischaemia

The most exciting potential use for glycine-site antagonists is that of neuroprotection against brain damage resulting from ischaemia, hypoxia or traumatic brain injury. Kynurenic acid itself can cross the blood–brain barrier to a limited extent and protect against damage induced by transient forebrain ischaemia. Several analogues, including L695902 and L701324, GV150526A, RPR104632 and ZD9379, are now in, or are likely to enter clinical trials. GV150526A reduced the neuronal damage following focal cerebral ischaemia in rats by 78% (Ref. 47), with a reduction of more than 50% when the drug was administered 6 h after the insult. GV150526A and ZD9379 both entered Phase I and II trials in 1996 and results should be available in the near future. Data on the nosology and safety of GV150526A in 66 patients indicate that GV150526A

REVIEW produces no significant nervous or cardiovascular adverse effects up to doses of 800 mg kg21 with subsequent infusions to maintain neuroprotective levels48. The promise of GV150526A is such that a series of analogues has recently been produced; several are potent glycine-site antagonists and systemically active anticonvulsants. One of these, 3-[2 (norbornylaminocarbonyl)ethenyl]-4,6-dichloroindole-2carboxylic acid has a Ki of only 19 nM at the glycine B site49. The Zeneca compound ZD9379 has a half-life of 34 h in rats, a fact that might contribute to its neuroprotective properties. About 50% protection was afforded 24 h after a dose of 10 mg kg21 given 30 min after middle cerebral artery occlusion, followed by a 4 h infusion, in rats50. Unlike dizocilpine or phencyclidine, neither GV150526A nor ZD9379 have induced neuronal damage and vacuolization, although ZD9379 induced significant ataxia and sedation. Other indications HIV

Chronic neurodegenerative disorders might owe part of the neuronal damage to increased activity at glutamate receptors, raising the possibility that NMDA or other receptor antagonists might be of value. There is overwhelming evidence for an involvement of NMDA receptors in the dementia associated with HIV (Ref. 26), which afflicts over 20% of those infected. The neuro-inflammation that accompanies CNS AIDS results in a large increase in the level of cerebral quinolinic acid, which might account for the activation of NMDA receptors. Parkinson’s disease

NMDA receptor blockers can reduce the severity of parkinsonism in animal models and humans51, in which there is neurochemical evidence for altered kynurenine metabolism52. The channel blockers and the polyamine site ligand ifenprodil can reduce symptoms of Parkinson’s disease, but side-effects only allow limited dosage. However, with the efficacy of these agents as ‘proof of principle’, it seems likely that the safer kynurenic acid derivatives acting at the glycine site of the NMDA receptor will prove more useful in practice as adjuncts to the present dopamine-based therapies. As yet it is unclear whether glutamate receptor antagonists will slow or prevent neuronal degeneration in this disorder. Schizophrenia

Marked changes in the number and subunit composition of glutamate and glycine receptors in schizophrenic patients suggest a role for glutamatergic hypofunction, which is supported by the beneficial effects of glycine-site agonists in some cases53. L701324 (1.1 mg kg21, administered orally) reduces amphetamine-induced hyperactivity but has no effect on normal locomotion and does not induce catalepsy at a 100 times greater dose. This profile is similar to the atypical antipsychotic drugs that reduce schizophrenic symptoms without inducing extrapyramidal signs. Presumably, glycine-site agonists ameliorate schizophrenia by downregulating the receptors, whereas L701324 achieves a therapeutic effect by blocking the receptors.

Epilepsy

Because activation of glutamate receptors seems important in the generation and spread of epileptiform activity, glutamate receptor antagonists should be effective anticonvulsants. All the glycine site antagonists tested to date can prevent seizures arising from a variety of triggers, including pentylenetetrazol and audiogenically-induced convulsions in DBA/2 mice, and several are being considered for development as anti-epileptic agents. Depression

Because the kynurenines are metabolites of tryptophan, changes in their concentration probably alter 5-HT metabolism. Conversely, the treatment of depression by selective 5-HT reuptake inhibitors (SSRIs) is very likely to change the balance between the amount of tryptophan used for 5-HT synthesis and that available for kynurenine synthesis. Could the behavioural changes induced by SSRIs be the result of changes in the levels of kynurenic acid, quinolinic acid, or other components of the kynurenine pathway? The physiological and pathological significance of kynurenines might be worth exploring in psychiatry and other areas of neuroscience beyond that of neuroprotection. Concluding remarks

The discovery of kynurenic acid has led to the development of powerful new agents that promise to emerge as some of the first effective treatments for brain neuroprotection as well as providing valuable adjunct or alternative therapies for other CNS disorders. This short review highlights only a few of these compounds and their therapeutic possibilities but, together with an increasing awareness of the role of quinolinic acid in inflammation-related neurodegeneration, it emphasizes the status of the kynurenine pathway as a major therapeutic target. Selected references 1 Vergun, O. et al. (1999) Glutamate-induced mitochondrial depolarization and perturbation of calcium homeostasis in cultured rat hippocampal neurones. J. Physiol. 519, 451–466 2 Stone, T.W. (1993) Neuropharmacology of quinolinic and kynurenic acids. Pharmacol. Rev. 45, 309–379 3 Stone, T.W. and Perkins, M.N. (1981) Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur. J. Pharmacol. 72, 411–412 4 Schwarcz, R. et al. (1983). Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science 219, 316–318 5 Perkins, M.N. and Stone, T.W. (1982) An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res. 247, 184–187 6 Stone, T.W. and Perkins, M.N. (1984) Actions of excitatory amino acids and kynurenic acid in the primate hippocampus: a preliminary study. Neurosci. Lett. 52, 335–340 7 Stone, T.W. (1990) Sensitivity of hippocampal neurones to kainic acid, and antagonism by kynurenate. Br. J. Pharmacol. 101, 847–852 8 Birch, P.J. et al. (1988) Kynurenic acid antagonises responses to NMDA via an action at the strychnine-insensitive glycine receptor. Eur. J. Pharmacol. 154, 85–87 9 Okuda, S. et al. (1998) 3-hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity. J. Neurochem. 70, 299–307 10 Behan, W.M.H. et al. (1999) Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl. Br. J. Pharmacol. 128, 1754–1760

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REVIEW 11 Baron, B.M. et al. (1990) Activity of 5,7-dichlorokynurenic acid, a potent antagonist at the NMDA receptor-associated glycine binding site. Mol. Pharmacol. 38, 554–561 12 Baron, B.M. et al. (1992) Potent indole- and quinoline-containing NMDA antagonists acting at the strychnine-insensitive glycine binding site. J. Pharmacol. Exp. Ther. 262, 947–956 13 Leeson, P.D. et al. (1992) 4-Amido-2-carboxytetrahydroquinolines. Structure–activity relationships for antagonism at the glycine site of the NMDA receptor. J. Med. Chem. 35, 1954–1968 14 Kulagowski, J.J. et al. (1994) 39-(Arylmethyl)- and 39-(aryloxy)-3-phenyl4-hydroxyquinolin-2(1H)-ones: orally active antagonists of the glycine site on the NMDA receptor. J. Med. Chem. 37, 1402–1405 15 Carling, R.W. et al. (1993) 3-Nitro-3,4-dihydro-3(1H )-quinolones – excitatory amino acid antagonists acting at glycine-site NMDA and AMPA receptors. J. Med. Chem. 36, 3397–3408 16 Rao, T.S. et al. (1993) Indole-2-carboxylates, novel antagonists of the NMDA-associated glycine recognition site – in vivo characterization. Neuropharmacology 32, 139–147 17 Glaxo (1993) Patent application 2266091 18 Boireau, A. et al. (1996) Neuroprotective effects of RPR104632, a novel antagonist at the glycine site of the NMDA receptor. Eur. J. Pharmacol. 300, 237–246 19 Zeneca Limited (1995) Patent application WO9511244 20 Bristow, L.J. et al. (1996) The atypical neuroleptic profile of the glycine/ N-methyl-D-aspartate receptor antagonist, L-701,324, in rodents. J. Pharmacol. Exp. Ther. 277, 578–585 21 Siegel, B.W. et al. (1996) Binding of the radiolabeled glycine site antagonist [3H]MDL 105,519 to homomeric NMDA-NR 1a receptors. Eur. J. Pharmacol. 312, 357–365 22 Jackson, P.F. et al. (1995) Synthesis and biological activity of a series of 4-aryl substituted benz[b]azepines: antagonists at the strychnine-insensitive glycine site. Bioorg. Med. Chem. Lett. 5, 3097–3100 23 Hokari, M. et al. (1996) Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acid. NeuroReport 8, 15–18 24 Heyes, M.P. et al. (1996) Human microglia convert L-tryptophan into the neurotoxin quinolinic acid. Biochem. J. 320, 595–597 25 Espey, M.G. et al. (1997) Activated human microglia produce the excitotoxin quinolinic acid. NeuroReport 8, 431–434 26 Heyes, M.P. et al. (1998) Sources of the neurotoxin quinolinic acid in the brain of HIV-1 infected patients and retrovirus-infected macaques. FASEB J. 12, 881–896 27 Nath, A. and Geiger, J. (1998) Neurobiological aspects of HIV infection: neurotoxic mechanisms. Prog. Neurobiol. 54, 19–33 28 Connick, J.H. et al. (1992) Nicotinylalanine increases cerebral kynurenic acid content and has anticonvulsant activity. Gen. Pharmacol. 23, 235–239 29 Russi, P. et al. (1992) Nicotinylalanine increases the formation of kynurenic acid in the brain and antagonizes convulsions. J. Neurochem. 59, 2076–2080 30 Harris, C.A. et al. (1998) Modulation of striatal quinolinate neurotoxicity by elevation of endogenous brain kynurenic acid. Br. J. Pharmacol. 124, 391–399 31 Miranda, A.F. et al. (1999) Quinolinic acid lesions of the nigrostriatal pathway: effect on turning behaviour and protection by elevation of endogenous kynurenic acid in Rattus norvegicus. Neurosci. Lett. 262, 81–84 32 Pellicciari, R. et al. (1994) Modulation of the kynurenine pathway in search for new neuroprotective agents. Synthesis and preliminary evaluation of (m-nitrobenzoyl)alanine, a potent inhibitor of kynurenine3-hydroxylase. J. Med. Chem. 37, 647–655 33 Chiarugi, A. et al. (1995) Comparison of the neurochemical and behavioural effects resulting from the inhibition of kynurenine hydroxylase and/or kynureninase. J. Neurochem. 65, 1176–1183 34 Chiarugi, A. et al. (1996) Kynurenine disposition in blood and brain of mice: effects of selective inhibitors of kynurenine hydroxylase and kynurenase. J. Neurochem. 67, 692–698 35 Speciale, C. et al. (1996) (R,S)-3,4-Dichlorobenzoylalanine (FCE 28833A)

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causes a large and persistent increase in brain kynurenic acid levels in rats. Eur. J. Pharmacol. 315, 263–267 Rover, S. et al. (1997) Synthesis and biochemical evaluation of N-(4phenylthiazol-2-yl)benzenesulfonamides as high-affinity inhibitors of kynurenine 3-hydroxylase. J. Med. Chem. 40, 4378–4385 Cozzi, R. et al. (1999) Kynurenine hydroxylase inhibitors reduce ischaemic brain damage: studies with (m-nitrobenzoyl)alanine and 3,4dimethoxy-[N-4-(nitrophenyl)thiazol-2-yl]-benzenesulfonamide (Ro 61-8048) in models of focal or global ischaemia. J. Cereb. Blood Flow Metab. 19, 771–777 Chiarugi, A. and Moroni, F. (1999) Quinolinic acid formation in immunoactivated mice: studies with (m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[N-4-(3-nitrophenyl)thiazol-2-yl[benzenesulphonamide (Ro61-8048), two potent and selective inhibitors of kynurenine hydroxylase. Neuropharmacology 38, 1225–1233 Chiarugi, A. and Moroni, F. (1999) Inhibition of quinolinic acid synthesis in experimental allergic encephalomyelitis by kynurenine hydroxylase inhibitors. Soc. Neurosci. Abstr. 25, 697 Heidempergher, F. et al. (1999) Pyrrolo[3,2c]quinoline derivatives: a new class of kynurenine 3-hydroxylase inhibitors. Farmaco 54, 152–160 Giordani, A. et al. (1999) 4-Phenyl-4-oxo-butanoic acid derivatives as inhibitors of kynurenine 3-hydroxylase. Bioorg. Med. Chem. Lett. 8, 2907–2912 Carpenedo, R. et al. (1999) Kynurenic acid inhibits glutamate output in striatal dialysates. Soc. Neurosci. Abstr. 25, 2230 Scharfman, H.E. et al. (1999) Quantitative differences in the effects of de novo produced and exogenous kynurenic acid in rat brain slices. Neurosci. Lett. 274, 111–114 Reinhard, J.F., Jr et al. (1996) Effects of 540C91 [(E)-3-[2-(49-pyridyl)vinyl]-1H-indole], an inhibitor of hepatic tryptophan dioxygenase, on brain quinolinic acid in mice. Biochem. Pharmacol. 51, 159–163 Naritsin, D.B. et al. (1995) Metabolism of L-tryptophan to kynurenate and quinolinate in the central nervous system: effects of 6-chlorotryptophan and 4-chloro-3-hydroyxanthranilate. J. Neurochem. 65, 2217–2226 Luthman, J. et al. (1998) Effects of the 3-hydroxyanthranilic acid analogue NCR-631 on anoxia-, IL1b- and LPS-induced hippocampal pyramidal cell loss in vitro. Amino Acids 14, 263–269 Bordi, F. et al. (1997) The glycine antagonist GV150526 protects somatosensory evoked potentials and reduces the infarct area in the MCAO model of focal ischaemia in the rat. Exp. Neurol. 145, 425–433 Dyker, A.G. and Lees, K.R. (1999) Safety and tolerability of GV150526 (a glycine site antagonist at the NMDA receptor) in patients with acute stroke. Stroke 30, 986–992 Micheli, F. et al. (1999) Cycloalkyl indole-2-carboxylates as useful tools for mapping the ‘North-Eastern’ region of the glycine binding site associated with the NMDA receptor. Archiv. der Pharmazie 332, 73–80 Tatlisumak, T. et al. (1998) A glycine site antagonist, ZD9379, reduces number of spreading depressions and infarct size in rats with permanent middle cerebral artery occlusion. Stroke 29, 190–195 Blandini, F. and Greenamyre, J.T. (1999) Protective and symptomatic strategies for therapy of Parkinson’s disease. Drugs Today 35, 473–483 Ogawa, T. et al. (1992) Kynurenine pathway abnormalities in Parkinson’s disease. Neurology 42, 1702–1706 Tamminga, C.A. (1998) Schizophrenia and glutamatergic transmission. Crit. Rev. Neurobiol. 12, 21–36

Chemical names 540C91: E-3-[2-(49pyridyl)vinyl]-1H-indole L695902: 4-hydroxy-3-(carboxymethyl)-quinoline-2(1H)-one NCR631: 4,6-dibromo-3-hydroxyanthranilic acid

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