Towards the Development of AgoKirs: New Pharmacological Activators to Study K(ir)2.x Channel and Target Cardiac Disease

Inward rectifier potassium ion channels (I(K1)-channels) of the K(ir)2.x family are responsible for maintaining a stable negative resting membrane potential in excitable cells, but also play a role in processes of non-excitable tissues, such as bone development. I(K1)-channel loss-of-function, either congenital or acquired, has been associated with cardiac disease. Currently, basic research and specific treatment are hindered by the absence of specific and efficient K(ir)2.x channel activators. However, twelve different compounds, including approved drugs, show off-target I(K1) activation. Therefore, these compounds contain valuable information towards the development of agonists of K(ir) channels, AgoKirs. We reviewed the mechanism of I(K1) channel activation of these compounds, which can be classified as direct or indirect activators. Subsequently, we examined the most viable starting points for rationalized drug development and possible safety concerns with emphasis on cardiac and skeletal muscle adverse effects of AgoKirs. Finally, the potential value of AgoKirs is discussed in view of the current clinical applications of potentiators and activators in cystic fibrosis therapy.