Pharmacological and molecular characterization of a chalcone analogue derived from a Senecio nutans metabolite: Modulation of Ca V 1.2 and K Ca 1.1 channels in hypertensive rats

Background and Purpose In this study, we evaluated the beneficial vascular effects of a newly semi‐synthesized chalcone derived from the Senecio nutans metabolite‐1 [4‐hydroxy‐3‐(3‐methyl‐2‐butenyl) acetophenone] in hypertensive rats. We investigated chalcone (CHAL13) through functional assays in spontaneously hypertensive rat (SHR) aorta. We also used fluorescence microscopy, RT‐qPCR, molecular docking and X‐ray crystallography. Key Results CHAL13‐induced vasorelaxation was unaffected by endothelial removal or inhibition of the eNOS–NO–sGC–cGMP signalling pathway in SHR. CHAL13 reduced extracellular Ca 2+ influx in Ca 2+ ‐free medium and decreased KCl‐induced intracellular Ca 2+ increases in primary vascular smooth muscle cells (pVSMCs). CHAL13 also suppressed the contraction induced by the Ca V 1.2 agonist Bay‐K8644 in SHR aortic rings, supporting a direct inhibitory effect on vascular Ca V 1.2 channels. Notably, activation of K Ca , K V and K ATP channels contributed significantly to CHAL13's vasorelaxant effect. Compared with its precursor metabolite, CHAL13 exhibited stronger interactions with the pore‐forming α 1C subunit of the Ca V 1.2 channel, near the binding site of voltage‐gated calcium channel blockers, and with the α 1 subunit of the K Ca 1.1 channel, near the binding site of known channel activators. CHAL13 also showed predicted interactions with K V 1.2 and vascular K ATP channels. Aortic tissues treated with CHAL13 showed upregulated expression of Kcnmb1 and Kcna5 transcripts, which are associated with vascular relaxation. Conclusions and Implications CHAL13 exerts a vasorelaxant effect primarily through Ca V 1.2 channel blockade and coordinated activation of multiple K + channel subtypes, suggesting membrane hyperpolarization in vascular smooth muscle. Its favourable chemical, pharmacokinetic and toxicological profiles support its potential as a novel antihypertensive scaffold.