Recent Advances in the Discovery of D-Amino Acid Oxidase Inhibitors and Their Therapeutic Utility in Schizophrenia

Dana      V. Ferraris; Takashi      Tsukamoto

Abstract

D-Amino acid oxidase (DAAO) catalyzes the oxidative metabolism of D-amino acids including D-serine, a full agonist at the allosteric glycine binding site of the NMDA receptor. D-serine was reported to improve negative and cognitive symptoms of schizophrenia, symptoms poorly addressed by the standard D2 antagonist therapies. Therefore, inhibition of DAAO has gained substantial interest as an effective way to increase D-serine levels in the brain. During the last several years, a growing number of structurally diverse DAAO inhibitors have been identified with significantly higher inhibitory potency compared to the conventional DAAO inhibitors. Some of these new generation of DAAO inhibitors are being evaluated for their ability to enhance D-serine levels in rodents and efficacy in animal models of schizophrenia. This article highlights the progress that has been made toward the discovery of DAAO inhibitors and recent efforts to exploit their therapeutic utility in schizophrenia.

Keywords: D-amino acid oxidase, D-serine, NMDA receptors, schizophrenia