D-Amino Acid Oxidase Inhibitors as a Novel Class of Drugs for Schizophrenia Therapy

Author(s): Silvia Sacchi , Elena Rosini , Loredano Pollegioni , Gianluca Molla .

Journal Name: Current Pharmaceutical Design

Volume 19 , Issue 14 , 2013

Abstract:

Over the years, accumulating evidence has indicated that D-serine represents the endogenous ligand for the glycinemodulatory binding site on the NR1 subunit of N-methyl-D-aspartate receptors in various brain areas. Cellular concentrations of D-serine are regulated by synthesis due to the enzyme serine racemase (isomerization reaction) and by degradation due to the same enzyme (elimination reaction) as well as by the FAD-containing flavoenzyme D-amino acid oxidase (DAAO, oxidative deamination reaction). Several findings have linked low levels of D-serine to schizophrenia: D-serine concentrations in serum and cerebrospinal fluid have been reported to be decreased in schizophrenia patients while human DAAO activity and expression are increased; oral administration of Dserine improved positive, negative, and cognitive symptoms of schizophrenia as add-on therapy to typical and atypical antipsychotics. This evidence indicates that increasing NMDA receptor function, perhaps by inhibiting DAAO-induced degradation of D-serine may alleviate symptoms in schizophrenic patients. Furthermore, it has been suggested that co-administration of D-serine with a human DAAO inhibitor may be a more effective means of increasing D-serine levels in the brain. Here, we present an overview of the current knowledge of the structure-function relationships in human DAAO and of the compounds recently developed to inhibit its activity (specifically the ones recently exploited for schizophrenia treatment).

Keywords: Schizophrenia, D-serine, NMDA receptor, inhibitors

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Article Details

VOLUME: 19
ISSUE: 14
Year: 2013
Page: [2499 - 2511]
Pages: 13
DOI: 10.2174/1381612811319140002
Price: $58

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