Rhamnocitrin isolated from Prunus padus var. seoulensis: A potent and selective reversible inhibitor of human monoamine oxidase A

Three flavanones and two flavones were isolated from the leaves of Prunus padus var. seoulensis by the activityguided screening for new monoamine oxidase (MAO) inhibitors. Among the compounds isolated, rhamnocitrin (5) was found to potently and selectively inhibit human MAO-A (hMAO-A, IC50 = 0.051 mu M) and effectively inhibit hMAO-B (IC50 = 2.97 mu M). The IC50 value of 5 for hMAO-A was the lowest amongst all natural flavonoids reported to date, and the potency was 20.2 times higher than that of toloxatone (1.03 mu M), a marketed drug. In addition, 5 reversibly and competitively inhibited hMAO-A and hMAO-B with K-i values of 0.030 and 0.91 mu M, respectively. Genkwanin (4) was also observed to strongly inhibit hMAO-A and hMAO-B (IC50 = 0.14 and 0.35 mu M, respectively), and competitively inhibit hMAO-A and hMAO-B (K-i = 0.097 and 0.12 mu M, respectively). Molecular docking simulation reveals that the binding affinity of 5 with hMAO-A (-18.49 kcal/mol) is higher than that observed with hMAO-B (0.19 kcal/mol). Compound 5 interacts with hMAO-A at four possible residues (Asn181, Gln215, Thr336, and Tyr444), while hMAO-B forms a single hydrogen bond at Glu84. These findings suggest that compound 5 as well as 4 can be considered as novel potent and reversible hMAO-A and/or hMAO-B inhibitors or useful lead compounds for future development of hMAO inhibitors in neurological disorder therapies.