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 o f tissues makes it an important therapeutic target for drug research. The existence of small molecules that modulate its activity has attrac ted a great deal of attention over the past several years. Progress ac hieved at understanding the structure-activity relationships of K-ATP openers, and their therapeutic utilities and mechanism of action are s ummarized in this review. The compounds combining the features of pote nt K-ATP openers cromakalim, pinacidil, and aprikalim retain the biolo gical profiles of their predecessors, indicating the classical K-ATP, openers may be expressing their biological effects through similar str uctural requirements. Based on these studies, a pharmacophore model wh ich incorporates a lipophilic residue, an electron deficient aromatic ring, and a hydrogen bonding site has been proposed. Although the firs t generation compounds have served as extremely useful tools., their t herapeutic utility is limited due to indiscriminate actions in a varie ty 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 i dentified 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 mole cular mechanism of action. (C) 1994 Wiley-Liss, Inc.