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Four derivatives (Chrysin <jats:bold>1\u20134<\/jats:bold>) were synthesised and a functional, electrophysiology and molecular docking approach was pursued to assess their binding mode to Ca<jats:sub>V<\/jats:sub>1.2 channels and their activity in vascular preparations. Methylation of the 5\u2010 and 7\u2010OH of the chrysin backbone caused a marked reduction of the Ca<jats:sup>2+<\/jats:sup> antagonistic potency and efficacy. However, C\u20108 derivatives showed biophysical features similar to those of the parent compound and, like nicardipine, bound with high affinity to and stabilised the Ca<jats:sub>V<\/jats:sub>1.2 channel in its inactivated state. The vasorelaxant effects of the four derivatives appeared vessel\u2010specific, 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<jats:sub>V<\/jats:sub>1.2 channel blockers.<\/jats:p>","DOI":"10.1002\/ardp.202400536","type":"journal-article","created":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T09:22:07Z","timestamp":1725614527000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Exploring the chemical space around chrysin to develop novel vascular Ca<sub>V<\/sub>1.2 channel blockers, promising vasorelaxant agents"],"prefix":"10.1002","volume":"357","author":[{"given":"Federica","family":"Falbo","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Sciences University of Calabria Arcavacata di Rende 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