Exploring the chemical space around chrysin to develop novel vascular Ca V 1.2 channel blockers, promising vasorelaxant agents

The flavonoid chrysin is an effective vascular Ca 1.2 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 f...

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Bibliographic Details
Published in:Archiv der Pharmazie (Weinheim) 2024-11, Vol.357 (11), p.e2400536
Main Authors: Falbo, Federica, Carullo, Gabriele, Panti, Alice, Spiga, Ottavia, Gianibbi, Beatrice, Ahmed, Amer, Campiani, Giuseppe, Ramunno, Anna, Aiello, Francesca, Fusi, Fabio
Format: Article
Language:English
Subjects:
Animals
Calcium Channel Blockers - chemical synthesis
Calcium Channel Blockers - chemistry
Calcium Channel Blockers - pharmacology
Calcium Channels, L-Type - drug effects
Calcium Channels, L-Type - metabolism
Flavonoids - chemical synthesis
Flavonoids - chemistry
Flavonoids - pharmacology
Humans
Male
Molecular Docking Simulation
Molecular Structure
Rats
Structure-Activity Relationship
Vasodilator Agents - chemical synthesis
Vasodilator Agents - chemistry
Vasodilator Agents - pharmacology
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Summary:The flavonoid chrysin is an effective vascular Ca 1.2 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 1.2 channels and their activity in vascular preparations. Methylation of the 5- and 7-OH of the chrysin backbone caused a marked reduction of the Ca 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 1.2 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 1.2 channel blockers.
ISSN:0365-6233
1521-4184
DOI:10.1002/ardp.202400536