Biochemical Pharmacology 2009-12-01

Commentary: genome-based CNS drug discovery: D-amino acid oxidase (DAAO) as a novel target for antipsychotic medications: progress and challenges.

Michael Williams

Index: Biochem. Pharmacol. 78(11) , 1360-5, (2009)

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Abstract

Antipsychotics, the drugs used currently for the treatment of schizophrenia, produce their therapeutic effects via the blockade of dopamine receptors. These compounds are, however, limited in their therapeutic efficacy and have side effect liabilities that also limit their use. Agents that produce antipsychotic effects by enhancing NMDA receptor function represent a viable alternative to dopamine antagonists. D-serine, is the prototype of this approach acting as a positive allosteric modulator of the NMDA receptor to enhance antipsychotic efficacy in the clinic. A newer approach to modulating NMDA receptor function, identified by gene association studies, is pLG72/DAOA (D-amino acid oxidase activator) a peptide that modulates D-amino acid oxidase (DAAO) activity, increasing endogenous levels of D-serine. While the initial association of DAOA with schizophrenia and its functional effects on DAAO activity have not been replicated, its identification has led to the development of several DAAO inhibitors, e.g., AS057278, CBIO and Compound 8, that are active in animal models of antipsychotic action. The complications in validating the G72 association with schizoprenia highlight the inherent challenges in translating gene-based, disease-related associations to drug discovery targets.