Advances in the structure‐activity relationships, mechanisms of action, and therapeutic utilities of ATP‐sensitive potassium channel openers

The presence of ATP‐sensitive potassium channel (K ATP ) in a variety of tissues makes it an important therapeutic target for drug research. The existence of small molecules that modulate its activity has attracted a great deal of attention over the past several years. Progress achieved at understanding the structure‐activity relationships of K ATP openers, and their therapeutic utilities and mechanism of action are summarized in this review. The compounds combining the features of potent K ATP openers cromakalim, pinacidil, and aprikalim retain the biological profiles of their predecessors, indicating the classical K ATP openers may be expressing their biological effects through similar structural requirements. Based on these studies, a pharmacophore model which incorporates a lipophilic residue, an electron deficient aromatic ring, and a hydrogen bonding site has been proposed. Although the first generation compounds have served as extremely useful tools., their therapeutic utility is limited due to indiscriminate actions in a variety of tissues. Tissue selective K ATP openers are required to advance these compounds into clinical practice. Progress made at the discovery of selective K ATP openers that might be useful for the treatment of ischemic heart disease, urinary incontinence, and asthma is described in this article. The molecular mechanism of action of K ATP openers is far from being understood. A binding site for these agents has been identified in the rat aortic smooth muscle cells and intact rat aortic tissue. However, the relationship of this binding site to K ATP is not understood at the present time. Further work is needed to explore the clinical utility of tissue selective agents and understand their molecular mechanism of action. © 1994 Wiley‐Liss, Inc.