A multitarget semi-synthetic derivative of the flavonoid morin with improved in vitro vasorelaxant activity: Role of Cav1.2 and KCa1.1 channels

Ca(v)1.2 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 Ca2+ antagonists to increase the flavonoid vasorelaxant activity. The effects of morin and its derivatives were assessed on Ca(v)1.2 and K(C)(a)1.1 channels, both in vitro and in silico, as well as on the contractile responses of rat aorta rings. All compounds were effective Ca(v)1.2 channel blockers, positioning in the alpha(1C) subunit region where standard blockers bind. Among the four newly synthesized morin derivatives, the penta-acetylated morin-1 was the most efficacious Ca2+ antagonist, presenting a vasorelaxant profile superior to that of the parent compound and, contrary to morin, antagonized also the release of Ca2+ from the sarcoplasmic reticulum; surprisingly, it also stimulated K(C)a1.1 channel current. Computational analysis demonstrated that morin-1 bound close to the K(C)a1.1 channel 56 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.

Automated summary

In this study, morin derivatives bearing the nitrophenyl moiety of dihydropyridine Ca2+ antagonists were synthesized to increase flavonoid vasorelaxant activity. Among the newly synthesized morin derivatives, penta-acetylated morin-1 was the most efficacious Ca2+ antagonist with a superior vasorelaxant profile compared to the parent compound, and it also stimulated K(C)a1.1 channel current. These findings suggest a new avenue for the synthesis of valuable multi-functional, vasorelaxant morin derivatives capable of targeting pathways underlying hypertension pathogenesis.