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. (C) 1994 Wiley-Liss, Inc.