D-amino acid oxidase inhibitors as a novel class of drugs for schizophrenia therapy.

Abstract

Over the years, accumulating evidence has indicated that D-serine represents the endogenous ligand for the glycine modulatory 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 D-serine 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).

• Authors: Silvia Sacchi, Elena Rosini, Loredano Pollegioni, Gianluca Molla
• Journal: Current pharmaceutical design (Curr Pharm Des) Vol. 19 Issue 14 Pg. 2499-511 ( 2013) ISSN: 1873-4286 [Electronic] United Arab Emirates
• PMID: 23116391 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Enzyme Inhibitors
• Ligands
• Receptors, N-Methyl-D-Aspartate
• Serine
• D-Amino-Acid Oxidase

Topics

• Brain (drug effects, enzymology, metabolism)
• D-Amino-Acid Oxidase (antagonists & inhibitors, chemistry, metabolism)
• Enzyme Inhibitors (administration & dosage, chemistry, therapeutic use)
• Humans
• Ligands
• Models, Molecular
• Protein Binding
• Protein Conformation
• Receptors, N-Methyl-D-Aspartate (metabolism)
• Schizophrenia (drug therapy, enzymology)
• Serine (metabolism)
• Structure-Activity Relationship
• Substrate Specificity