A multitarget semi-synthetic derivative of the flavonoid morin with improved in vitro vasorelaxant activity: Role of CaV1.2 and KCa1.1 channels

Abstract

Ca_V1.2 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_V1.2 and K_Ca1.1 channels, both in vitro and in silico, as well as on the contractile responses of rat aorta rings. All compounds were effective Ca_V1.2 channel blockers, positioning in the α_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_Ca1.1 channel current. Computational analysis demonstrated that morin-1 bound close to the K_Ca1.1 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.

Keywords: Ca(V)1.2 channels; Flavonoids; Hypertension; K(Ca)1.1 channels; Morin.