In silico screening, synthesis and in vitro determination of the biological activities of D-amino acid oxidase inhibitors

Abstract

Schizophrenia is a mental disorder with many clinical and therapeutic challenges. Current therapy is based on outdated pathological theories while most antipschycotic drugs have a significant side effect profile. New theories to explain the pathology of schizophrenia are being developed and novel drugs that act as improved antipsychotics are needed. D-Amino acid oxidase (DAAO) oxidises D-amino acids to ultimately produce the corresponding α-keto acids. D-Serine is an example of a substrate of DAAO and is a co agonist at the NMDA receptor. NMDA receptor hypo function has been implicated in the pathophysiology of schizophrenia. A strategy to improve NMDA receptor function is the inhibition of DAAO, and thereby to increase central D-serine levels. This approach serves as a potential treatment for schizophrenia. The small molecule, 3-hydroxycoumarin, is a potent inhibitor of DAAO, and represents an ideal lead for the development of novel DAAO inhibitors. Based on this, the present study investigated the DAAO inhibition potencies of series of synthetic and commercially available coumarin derivatives. Due to structural similarity to coumarin, a synthetic series of 3,4-dihydroisoquinolin-1(2H)-one derivatives was also included in this study. Among the 37 compounds that were evaluated, four inhibited porcine kidney DAAO with IC50 < 10 μM. The most potent inhibitor was 6,7-dihydroxycoumarin with an IC50 value of 0.224 μM. These values are significantly more potent than the reference DAAO inhibitor, 3-methylpyrazole-5-carboxylic acid (IC50 = 1.88 μM). Coumarin compounds are also known to be inhibitors of the monoamine oxidase (MAO) enzymes, which are well established targets for the treatment of depression and Parkinson’s disease. The series were thus evaluated as potential MAO inhibitors, and a number of high potency inhibitors were identified. Seven compounds inhibited the recombinant human MAOs with IC50 < 0.1 μM, with the most potent MAO-A and MAO-B inhibitors exhibiting IC50 values of 0.033 and 0.012 μM, respectively. These compounds are significantly more potent that the reference inhibitor, curcumin, with IC50 values of 5.02 and 2.56 μM for the inhibition of MAO-A and MAO-B, respectively. This study concludes that active DAAO and MAO inhibitors may serve as novel leads for the design of compounds that may find future application in the treatment of neuropsychiatric (e.g. schizophrenia, depression) and neurodegenerative disorders (e.g. Parkinson’s disease).