Hybridization between ivabradine and MEL55A results in compounds with improved potency on HCN channel isoforms

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Introduction A new series of phenylalkylamines structurally related to zatebradine and ivabradine was designed and prepared with the aim to find compounds showing preference or selectivity for individual HCN channel isoforms. Methods The new compounds are characterized by a different degree of conformational freedom, and by the presence of stereogenic centers in the region connecting the basic nitrogen to the veratrol moieties. Their effects were evaluated on h‐current mediated by homomeric mHCN1, mHCN2 and hHCN4 channels expressed in HEK 293 cells. Selected compounds were also assessed for effects on pacemaking activity in cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) and in zebrafish embryos. Results and Discussion All new compounds reduced h-current mediated by mHCN1, mHCN2 and hHCN4 channels. The most interesting compounds, derived from hybridization between MEL55A and ivabradine, were (R)‐1c and (S)‐1c. (R)‐1c preferentially inhibited mHCN2/hHCN4 relative to mHCN1, whereas (S)‐1c was a more potent but relatively non-selective blocker. Both compounds reduced pacemaking activity in hiPSC-derived cardiomyocytes and zebrafish embryos, demonstrating functional activity in both cellular and whole‐organism models.