In vitro and in vivo pharmacological profile of AS057278, a selective d-amino acid oxidase inhibitor with potential anti-psychotic properties

Adage, Tiziana; Trillat, Anne-Cécile; Quattropani, Anna; Perrin, Dominique; Cavarec, Laurent; Shaw, Jeffrey; Guerassimenko, Oxana; Giachetti, C; Greco, Béatrice; Chumakov, Ilya; Halazy, S.; Roach, Arthur; Zaratin, Paola

doi:10.1016/j.euroneuro.2007.06.006

Cited by 112 publications

(114 citation statements)

References 40 publications

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“…A number of recent studies focused on the development of new and effective hDAAO inhibitors as a treatment strategy for schizophrenia by modulating D-serine concentrations in the brain. [10][11][12][13] These studies reported on the synthesis and identification of new hDAAO inhibitors (mainly aromatic compounds that bind in the hDAAO active site, for a structural comparison see Ref. 13) and on their effect on rat brain D-serine concentration.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, and in agreement with the aforementioned model, hDAAO is now considered the target for a new class of drugs (hDAAO inhibitors) to treat schizophrenia. [10][11][12][13] Human DAAO shows the main properties of the dehydrogenase-oxidase class of flavoproteins and shares a low turnover number and a ternary complex (sequential) kinetic mechanism with pig kidney DAAO (pkDAAO, %85% sequence identity). 7 Indeed, this human flavoenzyme can be distinguished from the other known DAAOs because it is a stable homodimer even in the apoprotein form, because the binding of the FAD cofactor is the weakest among the known DAAOs (K d value is in the micromolar range) 1,7 and because it specifically interacts with pLG72 (which is expressed on primates only).…”

Section: Introductionmentioning

confidence: 99%

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Effect of ligand binding on human D‐amino acid oxidase: Implications for the development of new drugs for schizophrenia treatment

et al. 2010

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In human brain the flavoprotein D-amino acid oxidase (hDAAO) is responsible for the degradation of the neuromodulator D-serine, an important effector of NMDA-receptor mediated neurotransmission. Experimental evidence supports the concept that D-serine concentration increase by hDAAO inhibition may represent a valuable therapeutic approach to improve the symptoms in schizophrenia patients. This study investigated the effects on hDAAO conformation and stability of the substrate D-serine (or of the pseudo-substrate trifluoro-D-alanine), the FAD cofactor, and two inhibitors (benzoate, a classical substrate-competitive inhibitor and the drug chlorpromazine (CPZ), which competes with the cofactor). We demonstrated that all these compounds do not alter the interaction of hDAAO with its physiological partner pLG72. The ligands used affect the tertiary structure of hDAAO differently: benzoate or trifluoro-D-alanine binding increases the amount of the holoenzyme form in solution and stabilizes the flavoprotein, while CPZ binding favors a protein conformation resembling that of the apoprotein, which is more sensitive to degradation. Interestingly, the apoprotein form of hDAAO binds the substrate D-serine: this interaction increases FAD binding thus increasing the amount of active holoenzyme in solution. Benzoate and CPZ similarly modify the short-term cellular D-serine concentration but affect the cellular concentration of hDAAO differently. In conclusion, the different alteration of hDAAO conformation and stability by the ligands used represents a further parameter to take into consideration during the development of new drugs to cope schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of ligand binding on human D‐amino acid oxidase: Implications for the development of new drugs for schizophrenia treatment

et al. 2010

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“…Adage's group reported a slight increase in D-serine levels in rat brain following intravenous administration of a pyrazole-3-carboxylate based DAAO inhibitor (AS057278) alone [39], indicating that this effect may be due to its ability to penetrate the blood-brain barrier. Furthermore, Smith et al [40] have developed the novel DAAO inhibitor 4H-thieno[3,2-b]pyrrole-5-carboxylic acid (IC 50 =145 nM for human, IC 50 =114 nM for rat).…”

Section: Discussionmentioning

confidence: 99%

Effects of D-Amino Acid Oxidase Inhibitor on the Extracellular D-Alanine Levels and the Efficacy of D-Alanine on Dizocilpine-Induced Prepulse Inhibition Deficits in Mice

Horio¹,

Fujita²,

Ishima³

et al. 2009

TOCCHEMJ

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D-Alanine, one of D-amino acids present in the mammalian brain, is a selective and potent agonist at the Nmethyl-D-aspartate (NMDA) receptors. Like D-serine, D-alanine is reported to be effective in the treatment of schizophrenia. However, orally given D-alanine is metabolized substantially by D-amino acid oxidase (DAAO), diminishing its oral bioavailability. In this study, we studied the effects of oral D-alanine administration with or without the novel DAAO inhibitor, 5-chloro-benzo[d]isoxazol-3-ol (CBIO), on the extracellular D-alanine levels in the brain and on the prepulse inhibition (PPI) deficits after administration of the NMDA receptor antagonist dizocilpine. Co-administration of CBIO (30 mg/kg) with D-alanine (100 mg/kg), but not D-alanine (100 mg/kg) alone, significantly attenuated dizocilpine (0.1 mg/kg)-induced PPI deficits in mice. The in vivo microdialysis study of the conscious and free moving mice revealed that co-administration of CBIO (30 mg/kg) significantly increased extracellular levels of D-alanine in the frontal cortex after oral administration of D-alanine (100 mg/kg). These findings suggest that co-administration of CBIO can increase the bioavailability of D-alanine after oral administration of D-alanine, and that co-administration of CBIO can enhance the efficacy of D-alanine on dizocilpine-induced PPI deficits. Therefore, combination of D-alanine and a DAAO inhibitor such as CBIO offers new therapeutic potential for treatment of schizophrenia.

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“…More currently, Adage and co-workers have communicated that 1 has the potential for anti-psychotic action toward both cognitive and positive symptoms of schizophrenia. 20 N-Aryl derivatives of 1 such as the N-substituted benzyl derivative 2 and the pyrazole organotin(IV) ester 3 also display desirable physicochemical properties. 21,22 Like the…”

Section: Methodsmentioning

confidence: 99%

1,3-Dipolar cycloadditions of 2-thio-3-chloroacrylamides with diazoalkanes

2010

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In vitro and in vivo pharmacological profile of AS057278, a selective d-amino acid oxidase inhibitor with potential anti-psychotic properties

Cited by 112 publications

References 40 publications

Effect of ligand binding on human D‐amino acid oxidase: Implications for the development of new drugs for schizophrenia treatment

Effect of ligand binding on human D‐amino acid oxidase: Implications for the development of new drugs for schizophrenia treatment

Effects of D-Amino Acid Oxidase Inhibitor on the Extracellular D-Alanine Levels and the Efficacy of D-Alanine on Dizocilpine-Induced Prepulse Inhibition Deficits in Mice

1,3-Dipolar cycloadditions of 2-thio-3-chloroacrylamides with diazoalkanes

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