A multitarget semi-synthetic derivative of the flavonoid morin with improved in vitro vasorelaxant activity: Role of CaV1.2 and KCa1.1 channels.
Biochem Pharmacol
; 185: 114429, 2021 03.
Article
em En
| MEDLINE
| ID: mdl-33513341
ABSTRACT
CaV1.2 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 CaV1.2 and KCa1.1 channels, both in vitro and in silico, as well as on the contractile responses of rat aorta rings. All compounds were effective CaV1.2 channel blockers, positioning in the α1C 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 KCa1.1 channel current. Computational analysis demonstrated that morin-1 bound close to the KCa1.1 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Vasodilatadores
/
Flavonoides
/
Sistemas de Liberação de Medicamentos
/
Canais de Cálcio Tipo L
/
Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta
Limite:
Animals
Idioma:
En
Revista:
Biochem Pharmacol
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Itália