Molecular pharmacology of mineralocorticoid receptor antagonists: The role of co-regulators

Mineralocorticoid receptor (MR) antagonists have shown remarkable benefits in the treatment of cardiovascular disease. However, their underutilization in clinical practice may be attributed to concerns regarding the risk of hyperkalemia. An ideal selective MR modulator would inhibit the detrimental effects of MR in non-epithelial cells of the cardiovascular system while sparing its physiological function in kidney epithelial cells, thereby reducing the risk of adverse events. To address this issue, a new generation of non-steroidal MR antagonists, including esaxereneone, balcinrenone, ocedurenone, and finerenone, has been developed with distinct molecular structures and pharmacology. They share a mechanism of action that is different from the previously developed steroidal MR antagonists, leading to altered co-regulator interaction, potentially involving conformational changes of the receptor. Interfering with MR co-regulator interaction or the co-regulator itself may enable selective targeting of downstream signaling cascades and – in the long term – lead to more personalized medicine. In this review article, we summarize what is currently known about the mechanisms of action of the different MR antagonists with a focus on MR co-factor interaction and what may be inferred from this for future developments.