A multitarget semi-synthetic derivative of the flavonoid morin with improved in vitro vasorelaxant activity: Role of Ca1.2 and K1.1 channels.

Ca1.2 channels play a fundamental role in the regulation of vascular smooth muscle tone. The aim of the present study was to synthesize morin derivatives bearing the nitrophenyl moiety of dihydropyridine Ca antagonists to increase the flavonoid vasorelaxant activity. The effects of morin and its derivatives were assessed on Ca1.2 and K1.1 channels, both in vitro and in silico, as well as on the contractile responses of rat aorta rings. All compounds were effective Ca1.2 channel blockers, positioning in the α subunit region where standard blockers bind. Among the four newly synthesized morin derivatives, the penta-acetylated morin-1 was the most efficacious Ca antagonist, presenting a vasorelaxant profile superior to that of the parent compound and, contrary to morin, antagonized also the release of Ca from the sarcoplasmic reticulum; surprisingly, it also stimulated K1.1 channel current. Computational analysis demonstrated that morin-1 bound close to the K1.1 channel S6 segment. In conclusion, these findings open a new avenue for the synthesis of valuable multi-functional, vasorelaxant morin derivatives capable to target several pathways underpinning the pathogenesis of hypertension.