Exploring the chemical space around chrysin to develop novel vascular CaV1.2 channel blockers, promising vasorelaxant agents.

Abstract

The flavonoid chrysin is an effective vascular Ca_V1.2 channel blocker. The aim of this study was to explore the chemical space around chrysin to identify the structural features that can be modified to develop novel and more effective blockers. Four derivatives (Chrysin 1-4) were synthesised and a functional, electrophysiology and molecular docking approach was pursued to assess their binding mode to Ca_V1.2 channels and their activity in vascular preparations. Methylation of the 5- and 7-OH of the chrysin backbone caused a marked reduction of the Ca²⁺ antagonistic potency and efficacy. However, C-8 derivatives showed biophysical features similar to those of the parent compound and, like nicardipine, bound with high affinity to and stabilised the Ca_V1.2 channel in its inactivated state. The vasorelaxant effects of the four derivatives appeared vessel-specific, addressing the molecules' derivatization towards different targets. In conclusion, the scaffold of chrysin may be considered a valuable starting point for the development of innovative vascular Ca_V1.2 channel blockers.