Morin is a vasorelaxant flavonoid, whose activity is ascribable to CaV1.2 channel blockade that, however, is weak as compared to that of clinically used therapeutic agents. A conventional strategy to circumvent this drawback is to synthesize new derivatives differently decorated and, in this context, morin-derivatives able to interact with CaV1.2 channels were found by employing the potential of PLATO in target fishing and reverse screening. Three different derivatives (5a-c) were selected as promising tools, synthesized, and investigated in in vitro functional studies using rat aorta rings and rat tail artery myocytes. 5a-c were found more effective vasorelaxant agents than the naturally occurring parent compound and antagonized both electro- and pharmaco-mechanical coupling in an endothelium-independent manner. 5a, the series’ most potent, reduced also Ca2+ mobilization from intracellular store sites. Furthermore, 5a≈5c > 5b inhibited Ba2+ current through CaV1.2 channels. However, compound 5a caused also a concentration-dependent inhibition of KCa1.1 channel currents.

Artificial intelligence-driven identification of morin analogues acting as CaV1.2 channel blockers: Synthesis and biological evaluation

Federica Falbo;Francesca Aiello
;
2023-01-01

Abstract

Morin is a vasorelaxant flavonoid, whose activity is ascribable to CaV1.2 channel blockade that, however, is weak as compared to that of clinically used therapeutic agents. A conventional strategy to circumvent this drawback is to synthesize new derivatives differently decorated and, in this context, morin-derivatives able to interact with CaV1.2 channels were found by employing the potential of PLATO in target fishing and reverse screening. Three different derivatives (5a-c) were selected as promising tools, synthesized, and investigated in in vitro functional studies using rat aorta rings and rat tail artery myocytes. 5a-c were found more effective vasorelaxant agents than the naturally occurring parent compound and antagonized both electro- and pharmaco-mechanical coupling in an endothelium-independent manner. 5a, the series’ most potent, reduced also Ca2+ mobilization from intracellular store sites. Furthermore, 5a≈5c > 5b inhibited Ba2+ current through CaV1.2 channels. However, compound 5a caused also a concentration-dependent inhibition of KCa1.1 channel currents.
Morin Target fishing CaV1.2 channels Endothelium Ca2+ mobilization Docking simulations
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11770/341607
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