The insulin-releasing agent quercetin-3-oleate stimulates Ca1.2 channels similarly to quercetin, though with a reduced vasorelaxant activity.

The synthetic derivative quercetin-3-oleate (AV2), a partial agonist of the G-protein-coupled receptor 40 (GPR40), and its parent compound quercetin, a stimulator of Ca1.2 channels, promote insulin secretion from INS-1 pancreatic β cells. An in vitro and in silico approach was pursued to assess whether the incorporation of oleic acid at the C3 position maintains quercetin stimulation of Ca1.2 channels (key to triggering insulin release) while reducing its vasorelaxant properties. In rat tail main artery myocytes, AV2, like quercetin, stimulated Ba currents via Ca1.2 channels (I), demonstrating favourable interaction in molecular docking analyses and molecular dynamics simulations. Although AV2 also stimulated K currents via K1.1 channels (I), its vasorelaxant effect in vascular rings was significantly lower than that of quercetin. AV2 exhibited a positive inotropic effect and increased the frequency of Langendorff-perfused isolated rat hearts, albeit at concentrations one order of magnitude higher than those required for significant I stimulation. In in vitro settings, AV2 maintained a significant HO-induced radical scavenging activity. In conclusion, the conjugation of oleic acid with the dietary flavonoid quercetin in AV2 attenuated its spasmolytic effects on vascular smooth muscle, without affecting its I stimulatory activity. This, along with its GPR40 activation, highlights AV2 as a bifunctional agent with the potential to improve selective insulin secretion with minimal vascular effect.