KATP channel openers:: Structure-activity relationships and therapeutic potential

ATP-sensitive potassium channels (K-ATP channels) are heteromeric complexes of pore-forming inwardly rectifying potassium channel subunits and regulatory sulforylurea receptor subunits. K-ATP channels were identified in a variety of tissues including muscle cells, pancreatic beta-cells, and various neurons. They are regulated by the intracellular ATP/ADP ratio; ATP induces channel inhibition and MgADP induces channel opening. Functionally, K-ATP channels provide a means of linking the electrical activity of a cell to its metabolic state. Shortening of the cardiac action potential, smooth muscle relaxation, inhibition of both insulin secretion, and neurotransmitter release are mediated via K-ATP channels. Given their many physiological functions, K-ATP channels represent promising drug targets. Sulforylureas like glibenclamide block K-ATP channels; they are used in the therapy of type 2 diabetes. Openers of K-ATP channels (KCOs), for example, relax smooth muscle and induce hypotension. KCOs are chemically heterogeneous and include as different classes as the benzopyrans, cyanoguanidines, thioformamides, thiadiazines, and pyridyl nitrates. Examples for new chemical entities more recently developed as KCOs include cyclobutenediones, dihydropyridine related structures, and tertiary carbinols. (C) 2003 Wiley Periodicals, Inc.