Laboratory of Biomolecular Science, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
J Med Chem. 2013 Mar 14;56(5):1894-907. doi: 10.1021/jm3017865. Epub 2013 Feb 22.
D-amino acid oxidase (DAO) is a degradative enzyme that is stereospecific for D-amino acids, including D-serine and D-alanine, which are potential coagonists of the N-methyl-D-aspartate (NMDA) receptor. Dysfunction of NMDA receptor-mediated neurotransmission has been implicated in the onset of various mental disorders such as schizophrenia. Hence, a DAO inhibitor that augments the brain levels of D-serine and/or D-alanine and thereby activates NMDA receptor function is expected to be an antipsychotic drug, for instance, in the treatment of schizophrenia. In the search for potent DAO inhibitor(s), a large number of compounds were screened in silico, and several compounds were estimated as candidates. These compounds were then characterized and evaluated as novel DAO inhibitors in vitro. The results reported in this study indicate that some of these compounds are possible lead compounds for the development of a clinically useful DAO inhibitor and have the potential to serve as active site probes to elucidate the structure-function relationships of DAO.
D-氨基酸氧化酶（DAO）是一种对 D-氨基酸具有立体特异性的降解酶，包括 D-丝氨酸和 D-丙氨酸，它们是 N-甲基-D-天冬氨酸（NMDA）受体的潜在共激动剂。NMDA 受体介导的神经递质传递功能障碍与各种精神障碍的发生有关，如精神分裂症。因此，一种能够增加大脑中 D-丝氨酸和/或 D-丙氨酸水平并激活 NMDA 受体功能的 DAO 抑制剂有望成为一种抗精神病药物，例如用于治疗精神分裂症。在寻找有效的 DAO 抑制剂的过程中，大量化合物在计算机上进行了筛选，其中一些化合物被认为是候选物。这些化合物随后在体外进行了表征和评估，作为新型 DAO 抑制剂。本研究报告的结果表明，这些化合物中的一些可能是开发临床有用的 DAO 抑制剂的先导化合物，并有可能作为活性位点探针，阐明 DAO 的结构-功能关系。
