Osthenol, a prenylated coumarin, as a monoamine oxidase A inhibitor with high selectivity.

Graphical abstract Highlights • Osthenol was a potent (IC 50 = 0.74 µM) and selective inhibitor for hMAO-A (SI > 81.1). • Osthenol was a reversible and competitive inhibitor (K i = 0.26 µM). • The binding affinity of osthenol for hMAO-A was greater than that for hMAO-B. • The 8-(3,3-dimethylallyl) group of osthenol increased its inhibitory activity against hMAO-A. • Osthenol can be a potential lead compound for design of novel reversible MAO-A inhibitors. Abstract Osthenol (6), a prenylated coumarin isolated from the dried roots of Angelica pubescens , potently and selectively inhibited recombinant human monoamine oxidase-A (hMAO-A) with an IC 50 value of 0.74 µM and showed a high selectivity index (SI > 81.1) for hMAO-A versus hMAO-B. Compound 6 was a reversible competitive hMAO-A inhibitor (K i = 0.26 µM) with a potency greater than toloxatone (IC 50 = 0.93 µM), a marketed drug. Isopsoralen (3) and bakuchicin (1), furanocoumarin derivatives isolated from Psoralea corylifolia L., showed slightly higher IC 50 values (0.88 and 1.78 µM, respectively) for hMAO-A than 6 , but had low SI values (3.1 for both). Other coumarins tested did not effectively inhibit hMAO-A or hMAO-B. A structural comparison suggested that the 8-(3,3-dimethylallyl) group of 6 increased its inhibitory activity against hMAO-A compared with the 6-methoxy group of scopoletin (4). Molecular docking simulations revealed that the binding affinity of 6 for hMAO-A (−8.5 kcal/mol) was greater than that for hMAO-B (−5.6 kcal/mol) and that of 4 for hMAO-A (−7.3 kcal/mol). Docking simulations also implied that 6 interacted with hMAO-A at Phe208 and with hMAO-B at Ile199 by carbon hydrogen bondings. Our findings suggest that osthenol, derived from natural products, is a selective and potent reversible inhibitor of MAO-A, and can be regarded a potential lead compound for the design of novel reversible MAO-A inhibitors. [ABSTRACT FROM AUTHOR]