Natural Modulators of Large-Conductance Calcium-Activated Potassium Channels

Large-conductance calcium-activated potassium channels, also known as BK or Maxi-K channels, occur in many types of cell, including neurons and myocytes, where they play an essential role in the regulation of cell excitability and function. These properties open a possible role for BK-activators (also called BK-openers) and/or BK-blockers as effective therapeutic agents for different neurological, urological, respiratory and cardiovascular diseases. The synthetic benzimidazolone derivatives NS004 and NS1619 are the pioneer BK-activators and have represented the reference models which led to the design of several novel and heterogeneous synthetic BK-openers, while very few synthetic BK-blockers have been reported. Even today, the research towards identifying new BK-modulating agents is proceeding with great impetus and is giving an ever-increasing number of new molecules. Among these, also a handsome number of natural BK-modulator compounds, belonging to different structural classes, has appeared in the literature. The goal of this paper is to provide a possible simple classification of the broad structural heterogeneity of the natural BK-activating agents (terpenes, phenols, flavonoids) and blockers (alkaloids and peptides), and a concise overview of their chemical and pharmacological properties as well as potential therapeutic applications