Coumarin derivatives as inhibitors of D-amino acid oxidase and monoamine oxidase

D-Amino acid oxidase (DAAO) oxidises D-amino acids to ultimately produce the corresponding alpha-keto acids. The DAAO substrate, D-serine, is a co-agonist at NMDA receptors, while NMDA receptor hypo-function has been implicated in the pathophysiology of schizophrenia. Through the modulation of D-serine levels, the inhibition of DAAO represents a strategy to increase NMDA receptor function, and thus a potential treatment for schizophrenia. Literature reports that 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 DAAO inhibition by a 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 has also been included in this study. The results show that among 37 compound evaluated, four inhibit porcine kidney DAAO with IC50 < 10 mu M. The most potent inhibitors are 3,7-dihydroxycoumarin and 6,7-dihydroxycoumarin with an IC50 values of 0.167 and 0.224 mu M, respectively. These values are an improvement on that of the reference DAAO inhibitor, 3-methylpyrazole-5-carboxylic acid (IC50 = 1.88 mu M). Coumarin compounds are also known to inhibit the monoamine oxidase (MAO) enzymes, which are well established targets for the treatment of depression and Parkinson's disease. As DAAO and MAO are flavoenzymes, off-target inhibition may occur. The series were thus evaluated as potential MAO inhibitors, and a number of high potency inhibitors were identified. Seven compounds inhibit the recombinant human MAOs with IC50 < 0.1 mu M, with the most potent MAO-A and MAO-B inhibitors exhibiting IC50 values of 0.033 and 0.012 mu M, respectively. This is significantly more potent than the reference inhibitors, curcumin, isatin and toloxatone. 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).

Automated summary

Inhibition of DAAO represents a potential treatment for schizophrenia by increasing NMDA receptor function. The compounds studied in this research not only showed inhibition of DAAO, but also demonstrated potential as MAO inhibitors for the treatment of depression and Parkinson's disease.