(R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats

doi:10.1016/S0014-2999(96)00613-9

European Journal of Pharmacology

Volume 315, Issue 3, 21 November 1996, Pages 263-267

https://doi.org/10.1016/S0014-2999(96)00613-9 Get rights and content

Abstract

Kynurenic acid is an endogenous excitatory amino-acid receptor antagonist with neuroprotective and anticonvulsant properties. We demonstrate here that systemic administration of the new and potent kynurenine 3-hydroxylase inhibitor (R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a dose-dependent elevation in endogenous kynurenine and kynurenic acid levels in rat brain tissue. In hippocampal microdialysates, peak increases of 10- and 80-fold above basal kynurenic acid concentrations, respectively, were obtained after a single oral or intraperitoneal administration of 400 mg/kg FCE 28833A. After intraperitoneal treatment with FCE 28833A, extracellular brain kynurenic acid levels remained significantly elevated for at least 22 h, rendering this compound a far more effective enhancer of kynurenic acid levels than the previously described kynurenine 3-hydroxylase blocker m-nitrobenzoylalanine. FCE 28833A and similar molecules may have therapeutic value in diseases which are linked to a hyperfunction of excitatory amino-acid receptors.

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Cited by (95)

Therapeutic potential of targeting kynurenine pathway in neurodegenerative diseases
2023, European Journal of Medicinal Chemistry
Kynurenine pathway (KP), the primary pathway of L-tryptophan (Trp) metabolism in mammals, contains several neuroactive metabolites such as kynurenic acid (KA) and quinolinic acid (QA). Its imbalance involved in aging and neurodegenerative diseases (NDs) has attracted much interest in therapeutically targeting KP enzymes and KP metabolite-associated receptors, especially kynurenine monooxygenase (KMO). Currently, many agents have been discovered with significant improvement in animal models but only one aryl hydrocarbon receptor (AHR) agonist 30 (laquinimod) has entered clinical trials for treating Huntington's disease (HD). In this review, we describe neuroactive KP metabolites, discuss the dysregulation of KP in aging and NDs and summarize the development of KP regulators in preclinical and clinical studies, offering an outlook of targeting KP for NDs treatment in future.
Kynurenine emerges from the shadows – Current knowledge on its fate and function
2021, Pharmacology and Therapeutics
Kynurenine (KYN), a main metabolite of tryptophan in mammals, is a direct precursor of kynurenic acid, anthranilic acid and 3-hydroxykynurenine (3-HK). Under physiological conditions, KYN is produced endogenously mainly in the liver by tryptophan 2,3-dioxygenase (TDO). Tumorigenesis and inflammatory conditions increase the activity of another KYN synthetizing enzyme, indoleamine 2,3-dioxygenase (IDO). However, knowledge about the exogenous sources and the fate of KYN in mammals is still limited. While most papers deal with the contribution of KYN to pathologies of the central nervous system, its role in the periphery has almost been ignored. KYN is a ligand for the aryl hydrocarbon receptor (AhR). As a receptor for KYN and its downstream metabolites, AhR is involved in several physiological and pathological conditions, including inflammation and carcinogenesis. Recent studies have shown that KYN suppresses immune response and is strongly involved in the process of carcinogenesis and tumour metastasis. Thus, inhibition of activity of the enzymes responsible for KYN synthesis, TDO, IDO or genetic manipulation leading to reduction of KYN synthesis, could be considered as innovative strategies for improving the efficacy of immunotherapy. Surprisingly, however, genetic or pharmacological approaches for reducing tryptophan catabolism to KYN do not necessarily result in decrease of KYN level in the main circulation. This review aims to summarize the current knowledge of KYN fate and function and to emphasize its importance for vital physiological and pathological processes.
Advantages of brain penetrating inhibitors of kynurenine-3-monooxygenase for treatment of neurodegenerative diseases
2021, Archives of Biochemistry and Biophysics
Kynurenine-3-monooxygenase (KMO) is an important therapeutic target for several brain disorders that has been extensively studied in recent years. Potent inhibitors towards KMO have been developed and tested within different disease models, showing great therapeutic potential, especially in models of neurodegenerative disease. The inhibition of KMO reduces the production of downstream toxic kynurenine pathway metabolites and shifts the flux to the formation of the neuroprotectant kynurenic acid. However, the efficacy of KMO inhibitors in neurodegenerative disease has been limited by their poor brain permeability. Combined with virtual screening and prodrug strategies, a novel brain penetrating KMO inhibitor has been developed which dramatically decreases neurotoxic metabolites. This review highlights the importance of KMO as a drug target in neurological disease and the benefits of brain permeable inhibitors in modulating kynurenine pathway metabolites in the central nervous system.
In silico methods predict new blood-brain barrier permeable structure for the inhibition of kynurenine 3-monooxygenase
2020, Journal of Molecular Graphics and Modelling
Kynurenine 3-monooxygenase (KMO) regulates the levels of bioactive substances in the kynurenine pathway of tryptophan catabolism and its activity is tied to so many diseases that finding an appropriate inhibitor for KMO has become an urgent task. This especially proved to be difficult for the central nervous system related diseases due to the requirement that the supposed inhibitor should be both blood brain barrier permeable and should not cause hydrogen peroxide as a harmful side product. In this in silico study, we present our step-wise approach, whose starting point is based on the important experimental observations. To tackle the problem, a library of 7561938 structures was obtained from Zinc15 database utilizing the tranche browser. From this library, a subset of 501777 structures was determined with the considerations of their functional groups that constrain their applicability. Then, the binding affinity ranking of this set of structures was determined via virtual screening. Starting from the structures whose affinities are the highest among this subset, the ADMET properties were checked through in silico methods and the binding properties of the selected inhibitor candidates were further investigated via molecular dynamics simulations and MM/GBSA calculations. According to the computational results of this study, ZINC_71915355 has passed all the evaluations and is a potentially BBB permeable structure that can inhibit KMO. Additionally, ZINC_19827377 was identified as a new potential KMO inhibitor which may be more suitable for peripheral administration. From the in silico study presented herein, ZINC_71915355 and ZINC_19827377 structures, which showed high binding affinity without harmful H₂O₂ production, along with the tailored properties can now serve as powerful candidates for KMO inhibition and these hits are worth of further experimental validation.
LPS-induced cortical kynurenic acid and neurogranin-NFAT signaling is associated with deficits in stimulus processing during Pavlovian conditioning
2017, Journal of Neuroimmunology
Citation Excerpt :
These results suggest that inflammation may preferentially activate KYNA-Nrgn signaling in the mPFC. Moreover, our study is the first to show that pharmacological inhibition of KMO, which deviates kynurenine conversion toward KYNA (Erhardt et al., 2004; Justinova et al., 2013; Speciale et al., 1996), can effectively increase PKC-Nrgn phosphorylation in the mPFC. Supporting our findings, KMO null mice, which exhibit increased brain KYNA, also upregulates Nrgn mRNA expression (Erhardt et al., 2016).
The N-Methyl-d-Aspartate receptor (NMDAR) antagonist kynurenic acid (KYNA) and the post-synaptic calmodulin binding protein neurogranin (Nrgn) have been implicated in neurological and neuropsychiatric conditions including Alzheimer's disease and schizophrenia. This study indicates that systemic dual-lipopolysaccharide (LPS) injections increases KYNA in the medial prefrontal cortex (mPFC), which is accompanied with increased phosphorylation of nuclear factor kappa chain of activated B cells (NFκB) and activation of the nuclear factor of activated T- cells (NFAT). Our results also indicate that dual-LPS increases Nrgn phosphorylation and concomitantly reduces phosphorylation of calmodulin kinase-II (CaMKII). We confirmed that systemic blockade of kynurenine-3 monooxygenase in conjunction with kynurenine administration results in significant increases in Nrgn phosphorylation and a significant reduction of CaMKII phosphorylation in the mPFC. Consequently, dual-LPS administration induced significant impairments in stimulus processing during Pavlovian conditioning. Taken together, our study indicates that elevations in KYNA in the mPFC can directly regulate NMDA-Nrgn-CaMKII signaling, suggesting that neuroinflammatory conditions affecting this pathway may be associated with cognitive dysfunction.
Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders
2017, Biological Psychiatry
Kynurenine 3-monooxygenase converts kynurenine to 3-hydroxykynurenine, and its inhibition shunts the kynurenine pathway—which is implicated as dysfunctional in various psychiatric disorders—toward enhanced synthesis of kynurenic acid, an antagonist of both α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors. Possibly as a result of reduced kynurenine 3-monooxygenase activity, elevated central nervous system levels of kynurenic acid have been found in patients with psychotic disorders, including schizophrenia.
In the present study, we investigated adaptive—and possibly regulatory—changes in mice with a targeted deletion of Kmo (Kmo^–/–) and characterized the kynurenine 3-monooxygenase–deficient mice using six behavioral assays relevant for the study of schizophrenia.
Genome-wide differential gene expression analyses in the cerebral cortex and cerebellum of these mice identified a network of schizophrenia- and psychosis-related genes, with more pronounced alterations in cerebellar tissue. Kynurenic acid levels were also increased in these brain regions in Kmo^–/– mice, with significantly higher levels in the cerebellum than in the cerebrum. Kmo^–/– mice exhibited impairments in contextual memory and spent less time than did controls interacting with an unfamiliar mouse in a social interaction paradigm. The mutant animals displayed increased anxiety-like behavior in the elevated plus maze and in a light/dark box. After a D-amphetamine challenge (5 mg/kg, intraperitoneal), Kmo^–/– mice showed potentiated horizontal activity in the open field paradigm.
Taken together, these results demonstrate that the elimination of Kmo in mice is associated with multiple gene and functional alterations that appear to duplicate aspects of the psychopathology of several neuropsychiatric disorders.

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(R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats

Abstract

J. Biol. Chem.

Neuroscience

J. Biol. Chem.

Neurosci. Lett.

FEBS Lett.

Neurosci. Lett.

J. Biol. Chem.

Brain Res. Bull.

Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism

J. Neurochem.

Metabolism of 5-3H-kynurenine in the rat brain in vivo: evidence for the existence of a functional kynurenine pathway

J. Neurochem.

Metabolism of 5-³H-kynurenine in the rat brain in vivo: evidence for the existence of a functional kynurenine pathway