The flavonoid scaffold as a template for the design of modulators of the vascular Cav1.2 channels

• Published in: British journal of pharmacology 2011-11, Vol.164 (6), p.1684-1697
• Main Authors: Saponara, S, Carosati, E, Mugnai, P, Sgaragli, G, Fusi, F
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cav1.2 channel current; Medical sciences; myricetin; Pharmacology. Drug treatments; quercetin; rat tail artery myocyte; Research Papers; whole‐cell patch‐clamp
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2011.01476.x

BACKGROUND AND PURPOSE Previous studies have pointed to the plant flavonoids myricetin and quercetin as two structurally related stimulators of vascular Cav1.2 channel current (ICa1.2). Here we have tested the proposition that the flavonoid structure confers the ability to modulate Cav1.2 channels. EXPERIMENTAL APPROACH Twenty‐four flavonoids were analysed for their effects on ICa1.2 in rat tail artery myocytes, using the whole‐cell patch‐clamp method. KEY RESULTS Most of the flavonoids stimulated or inhibited ICa1.2 in a concentration‐ and voltage‐dependent manner with EC50 values ranging between 4.4 µM (kaempferol) and 16.0 µM (myricetin) for the stimulators and IC50 values between 13.4 µM (galangin) and 100 µM [(±)‐naringenin] for the inhibitors. Key structural requirements for ICa1.2 stimulatory activity were the double bond between C2 and C3 and the hydroxylation pattern on the flavonoid scaffold, the latter also determining the molecular charge, as shown by molecular modelling techniques. Absence of OH groups in the B ring was key in ICa1.2 inhibition. The functional interaction between quercetin and either the stimulator myricetin or the antagonists resokaempferol, crysin, genistein, and 5,7,2′‐trihydroxyflavone revealed that quercetin expressed the highest apparent affinity, in the low µM range, for Cav1.2 channels. Neither protein tyrosine kinase nor protein kinase Cα were involved in quercetin‐induced stimulation of ICa1.2. CONCLUSIONS AND IMPLICATIONS Quercetin‐like plant flavonoids were active on vascular Cav1.2 channels. Thus, the flavonoid scaffold may be a template for the design of novel modulators of vascular smooth muscle Cav1.2 channels, valuable for the treatment of hypertension and stroke.