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

Morin is a vasorelaxant flavonoid, whose activity is ascribable to Ca(V)1.2 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 Ca(V)1.2 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 approximate to 5c > 5b inhibited Ba2+ current through Ca(V)1.2 channels. However, compound 5a caused also a concentration-dependent inhibition of K(Ca)1.1 channel currents.