Comparison of the ß-Adrenergic Receptor Antagonists Landiolol and Esmolol: Receptor Selectivity, Partial Agonism, and Pharmacochaperoning Actions.

Blockage of ß1-adrenergic receptors is one of the most effective treatments in cardiovascular medicine. Esmolol was introduced some three decades ago as a short-acting ß1-selective antagonist. Landiolol is a more recent addition. Here we compared the two compounds for their selectivity for ß1-adrenergic receptors over ß2-adrenergic receptors, partial agonistic activity, signaling bias, and pharmacochaperoning action by using human embryonic kidney (HEK)293 cell lines, which heterologously express each human receptor subtype. The affinity of landiolol for ß1-adrenergic receptors and ß2-adrenergic receptors was higher and lower than that of esmolol, respectively, resulting in an improved selectivity (216-fold versus 30-fold). The principal metabolite of landiolol (M1) was also ß1-selective, but its affinity was very low. Both landiolol and esmolol caused a very modest rise in cAMP levels but a robust increase in the phosphorylation of extracellular signal regulated kinases 1 and 2, indicating that the two drugs exerted partial agonist activity with a signaling bias. If cells were incubated for ≥24 hours in the presence of ≥1 µM esmolol, the levels of ß1-adrenergic-but not of ß2-adrenergic-receptors increased. This effect was contingent on export of the ß1-receptor from endoplasmic reticulum and was not seen in the presence of landiolol. On the basis of these observations, we conclude that landiolol offers the advantage of: 1) improved selectivity and 2) the absence of pharmacochaperoning activity, which sensitizes cells to rebound effects upon drug discontinuation.