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Journal ArticleDOI

Synthesis and biological evaluation of D-amino acid oxidase inhibitors.

29 May 2008-Journal of Medicinal Chemistry (American Chemical Society)-Vol. 51, Iss: 12, pp 3357-3359
TL;DR: Oral administration of CBIO in conjunction with d-serine enhanced the plasma and brain levels of d-Serine in rats compared to the oral administration of d -serine alone.
Abstract: D-amino acid oxidase (DAAO) catalyzes the oxidation of D-amino acids including d-serine, a full agonist at the glycine site of the NMDA receptor. A series of benzo[ d]isoxazol-3-ol derivatives were synthesized and evaluated as DAAO inhibitors. Among them, 5-chloro-benzo[ d]isoxazol-3-ol (CBIO) potently inhibited DAAO with an IC50 in the submicromolar range. Oral administration of CBIO in conjunction with d-serine enhanced the plasma and brain levels of d-serine in rats compared to the oral administration of d-serine alone.
Citations
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Journal ArticleDOI
TL;DR: Substances regulating activation/inhibition of the NMDA receptor have been investigated in schizophrenia and major depression and are promising in therapeutic approaches of negative symptoms, cognition, and mood and should be investigated to elucidate neural mechanisms underlying efficacy.
Abstract: Severe psychiatric disorders such as schizophrenia are related to cognitive and negative symptoms, which often are resistant to current treatment approaches. The glutamatergic system has been implicated in the pathophysiology of schizophrenia and affective disorders. A key component is the dysfunction of the glutamatergic N-methyl-d-aspartate (NMDA) receptor. Substances regulating activation/inhibition of the NMDA receptor have been investigated in schizophrenia and major depression and are promising in therapeutic approaches of negative symptoms, cognition, and mood. In schizophrenia, add-on treatments with glycine, d-serine, d-alanine, d-cycloserine, d-amino acid oxidase inhibitors, glycine transporter-1 (GlyT-1) inhibitors (e.g., sarcosine, bitopertin) and agonists (e.g., LY2140023) or positive allosteric modulator (e.g., ADX71149) of group II metabotropic glutamate receptors (mGluRs) have been studied. In major depression, the NMDA receptor antagonists (e.g., ketamine, AZD6765), GluN2B subtype antagonists (e.g., traxoprodil, MK-0657), and partial agonists (e.g., d-cycloserine, GLYX-13) at the glycine site of the NMDA receptor have been proven to be effective in animal studies and first clinical trials. In addition, clinical studies of mGluR2/3 antagonist BCI-838 (a prodrug of BCI-632 (MGS0039)), mGluR2/3-negative allosteric modulators (NMAs) (e.g., RO499819, RO4432717), and mGluR5 NAMs (e.g., AZD2066, RO4917523) are in progress. Future investigations should include effects on brain structure and activation to elucidate neural mechanisms underlying efficacy of these drugs.

195 citations

Journal ArticleDOI
TL;DR: This review critically review the neurobiology of DAO, its involvement in schizophrenia, and the therapeutic value ofDAO inhibition and highlights issues that have a broader relevance beyond DAO itself.
Abstract: D-amino acid oxidase (DAO) is a flavoenzyme that metabolizes certain D-amino acids, notably the endogenous N-methyl D-aspartate receptor (NMDAR) co-agonist, D-serine. As such, it has the potential to modulate the function of NMDAR and to contribute to the widely hypothesized involvement of NMDAR signalling in schizophrenia. Three lines of evidence now provide support for this possibility: DAO shows genetic associations with the disorder in several, although not all, studies; the expression and activity of DAO are increased in schizophrenia; and DAO inactivation in rodents produces behavioural and biochemical effects, suggestive of potential therapeutic benefits. However, several key issues remain unclear. These include the regional, cellular and subcellular localization of DAO, the physiological importance of DAO and its substrates other than D-serine, as well as the causes and consequences of elevated DAO in schizophrenia. Herein, we critically review the neurobiology of DAO, its involvement in schizophrenia, and the therapeutic value of DAO inhibition. This review also highlights issues that have a broader relevance beyond DAO itself: how should we weigh up convergent and cumulatively impressive, but individually inconclusive, pieces of evidence regarding the role that a given gene may have in the aetiology, pathophysiology and pharmacotherapy of schizophrenia?

153 citations

Journal ArticleDOI
TL;DR: The complex regulation of endogenous NMDAR D-serine/glycine site agonists is outlined and their contribution to schizophrenia pathogenesis and their potential clinical utility are explored.

127 citations


Cites background from "Synthesis and biological evaluation..."

  • ...However, elevations in D-serine following DAO inhibition are considerably lower than with exogenous D-serine treatments (Smith et al., 2008; Ferraris et al., 2008) and since DAO is predominantly located in caudal brain regions (Moreno et al....

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  • ...However, elevations in D-serine following DAO inhibition are considerably lower than with exogenous D-serine treatments (Smith et al., 2008; Ferraris et al., 2008) and since DAO is predominantly located in caudal brain regions (Moreno et al., 1999) it remains to be determined if DAO inhibition can…...

    [...]

Journal ArticleDOI
TL;DR: Findings suggest that coadministration of CBIO significantly enhanced the efficacy of D-serine in attenuating PPI deficits by administration of dizocilpine, and coadministation of D -serine and a DAAO inhibitor has therapeutic potential for the treatment of schizophrenia.

126 citations

Journal ArticleDOI
TL;DR: Recent developments in utilizing DAAO are reviewed, including as a biocatalyst for resolving racemic amino acid mixtures, as a tool for biosensing, and as a new mechanism of herbicide resistance.

124 citations

References
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Journal ArticleDOI
TL;DR: A significant improvement in patients who received D-serine treatment revealed significant improvements in their positive, negative, and cognitive symptoms as well as some performance in Wisconsin Card Sorting Test (WCST).

717 citations

Journal ArticleDOI
TL;DR: Reduced levels of D-serine may play a role in the pathophysiology of schizophrenia, and serum D- and L-Serine levels might provide a measurable biological marker for schizophrenia.
Abstract: Background The hypofunction of theN-methyl-D-aspartate (NMDA) subtype of glutamate receptors has been implicated in the pathophysiology of schizophrenia. Several lines of evidence suggest thatD-serine may function as an endogenous agonist of the glycine site of the NMDA receptor. The aim of this study was to examine whether serum levels ofD-andL-serine in patients with schizophrenia are different from those of healthy controls. Methods Forty-two patients with schizophrenia and 42 age- and sex-matched healthy controls were enrolled in this study. Symptoms were assessed using the Brief Psychiatric Rating Scale. Serum levels of total serine andD-andL-serine were measured by high-performance liquid chromatography. Results Serum levels ofD-serine in the patients with schizophrenia were significantly (z= −3.30,P= .001) lower than those of healthy controls. In contrast, serum levels of total (DandL) serine (z= −2.40,P= .02) andL-serine(z= −2.49,P= .01) in the schizophrenic patients were significantly higher than those of controls. In addition, the percentage ofD-serine in the total serine in the schizophrenic patients was significantly (z=−4.78,P Conclusions Reduced levels ofD-serine may play a role in the pathophysiology of schizophrenia, and serumD- andL-serine levels might provide a measurable biological marker for schizophrenia.

462 citations

Journal ArticleDOI
TL;DR: The catalytic sites of D-amino acid oxidase and flavocytochrome b2 appear to have converged to a highly similar but enantiomeric architecture in order to catalvze similar reactions, although with opposite stereochemistry.
Abstract: D-amino acid oxidase is the prototype of the FAD-dependent oxidases. It catalyses the oxidation of D-amino acids to the corresponding alpha-ketoacids. The reducing equivalents are transferred to molecular oxygen with production of hydrogen peroxide. We have solved the crystal structure of the complex of D-amino acid oxidase with benzoate, a competitive inhibitor of the substrate, by single isomorphous replacement and eightfold averaging. Each monomer is formed by two domains with an overall topology similar to that of p-hydroxybenzoate hydroxylase. The benzoate molecule lays parallel to the flavin ring and is held in position by a salt bridge with Arg-283. Analysis of the active site shows that no side chains are properly positioned to act as the postulated base required for the catalytic carboanion mechanism. On the contrary, the benzoate binding mode suggests a direct transfer of the substrate alpha-hydrogen to the flavin during the enzyme reductive half-reaction.The active site Of D-amino acid oxidase exhibits a striking similarity with that of flavocytochrome b2, a structurally unrelated FMN-dependent flavoenzyme. The active site groups (if these two enzymes are in fact superimposable once the mirror-image of the flavocytochrome b2 active site is generated with respect to the flavin plane. Therefore, the catalytic sites of D-amino acid oxidase and flavocytochrome b2 appear to have converged to a highly similar but enantiomeric architecture in order to catalvze similar reactions (oxidation of alpha-amino acids or alpha-hydroxy acids), although with opposite stereochemistry.

269 citations

Journal ArticleDOI
TL;DR: It is suggested that synthetic or metabolic pathways of D-serine may be abnormal in the brain of drug-naive schizophrenic patients, supporting the NMDA receptor dysfunction hypothesis of schizophrenia.
Abstract: Several lines of evidence suggest that D-serine, an endogenous agonist of the glycine site on the NMDA receptors, might play a role in the pathophysiology of schizophrenia. The purpose of this study was to determine whether levels of D- and L-serine or D-serine ratio (D-serine/total serine) in cerebrospinal fluid (CSF) were altered in first episode and drug-naive schizophrenic patients. The CSF levels of D- and L-serine in 25 male first episode and drug-naive schizophrenic patients and 17 age-matched male healthy subjects were measured using a column-switching high performance liquid chromatography system. The percentage of D-serine in the total serine of patients was significantly (z = -2.01, p = 0.044) lower than that of controls. This study suggests that synthetic or metabolic pathways of D-serine may be abnormal in the brain of drug-naive schizophrenic patients, supporting the NMDA receptor dysfunction hypothesis of schizophrenia.

242 citations

Journal ArticleDOI
TL;DR: Reduced activity at NMDA receptors is implicated in the aetiology of schizophrenia, and drugs that increase activity at GlycineB sites may be of use as adjuncts to other classes of antipsychotic agent.
Abstract: Rationale Activation of “co-agonist” N-methyl-d-aspartate (NMDA) and GlycineB sites is mandatory for the operation of NMDA receptors, which play an important role in the control of mood, cognition and motor function.

225 citations