The Therapeutic Potential of D-Amino Acid Oxidase (DAAO) Inhibitors

Abstract

D-amino acid oxidase (DAAO) is a flavoenzyme that degrades D-amino acids through the process of oxidative deamination. DAAO regulation of D-amino acid levels has been associated with several physiological processes ranging from hormone secretion to synaptic transmission and cognition. Recent genetic studies have identified a mutation on chromosome 13 in schizophrenia patients that encodes two gene products (G30 and G72) that are associated with DAAO. Furthermore, DAAO expression and enzyme activity has been reported to be increased in post mortem brain tissue samples from patients with schizophrenia compared to healthy controls. D-serine, a D-amino acid that is regulated by DAAO, is a potent, endogenous co-agonist of the N-methyl-D-aspartic acid (NMDA) receptor. Because NMDA receptor dysfunction is thought to be involved in the positive (psychotic), negative and cognitive symptoms in schizophrenia, there has been much interest in developing potent and selective DAAO inhibitors for the treatment of this disease. Several research reports have been published that describe the synthesis and biological effects of novel, selective, small molecule inhibitors of DAAO. Many of these compounds have been shown, when given systemically, to increase D-serine concentrations in the blood and brain. However, the efficacy of these compounds in behavioral assays that measure antipsychotic potential and pro-cognitive effects in laboratory animals has been inconsistent. This article highlights and reviews research advances for DAAO inhibitors published in peer reviewed journals.

D-Amino-Acid Oxidase Inhibition Increases D-Serine Plasma Levels in Mouse But not in Monkey or Dog

“…Consequently, DAAO inhibition could also provide protection against potential toxic side effects from high doses of D-serine (Figure 1a). Several research groups have had an interest in identifying clinically viable DAAO inhibitors that could be given alone or in combination with D-serine to patients with schizophrenia (Adage et al, 2008;Duplantier et al, 2009;Ferraris et al, 2008;Ferraris and Tsukamoto, 2011;Smith et al, 2009Smith et al, , 2010. Even though there have been promising results when DAAO inhibitors are given in combination with D-serine, all studies have been in rodents (Ferraris and Tsukamoto, 2011).…”

D-Serine in Neuropsychiatric Disorders: New Advances

“…Furthermore, in contrast to the fairly robust effects reported with DSR administration in animal models, the reported behavioral effects of DAAO inhibitors are fairly modest and inconsistent (rev. in [186]). …”

“…Hashimoto et al [188] extended this finding by showing effects on cortical DSR and also demonstrated that coadministration of DSR (30 mg/kg) and CBIO reversed an MK-801-induced deficit in prepulse inhibition (PPI), whereas the 30 mg/kg dose of DSR had no effect on its own. Smith et al [186] showed that coadministration of compound 4 in conjunction with DSR elevates CSF and cortical DSR levels to a greater extent than administration of DSR alone in male rats. Overall, these findings suggest that DAAO inhibitors could be useful clinically for reducing the dose of DSR necessary for symptom improvement.…”

Therapeutic Uses of Amino Acids

“…The d-isomers that were found to be active in inhibiting bioilm formation were d-phenylalanine (Figure 2a The therapeutic potential of d-amino acid oxidase (DAAO) inhibitors, a lavoenzyme that degrades d-amino acids through the process of oxidative deamination, in schizophrenia patients has also been studied [9]. DAAO catalyses the metabolism of d-serine, a known full agonist at the allosteric glycine binding site of the N-methyl-d-aspartic acid (NMDA) (Figure 3) receptor, which has been reported to improve negative and cognitive symptoms of schizophrenia [10].…”

“…DAAO catalyses the metabolism of d-serine, a known full agonist at the allosteric glycine binding site of the N-methyl-d-aspartic acid (NMDA) (Figure 3) receptor, which has been reported to improve negative and cognitive symptoms of schizophrenia [10]. As a result, several studies have focused on the design and development of selective DAAO inhibitors, which when administered to schizophrenia patients have been shown to increase the concentrations of d-serine in the blood and the brain [9].…”