Selectivity Of Iptakalim On ATP-sensitive Potassium Channels

ATP-sensitive potassium channels (Katp channels) couple intracellular metabolic changes to the electrical activity of the plasma membrane, thus playing important roles in both physiological and pathological conditions. K_ATP channels are found in a wide variety of tissues, such as muscles, pancreatic islets, and neurons, regulating heart rate, blood vessel tone, insulin secretion, and neurotransmitter release. However, Just as the wide diversity and distribution of Katp channel subtypes in the body, the anti-hypertensive function of potassium channel openers (KCOs) that target vascular K_ATP channels often accompanied by other side effects that limit their clinical application.. Now a major problem in developing that these agents has been the limited its lack of tissue and channel selectivity. Therefore, the development of chemically novel, tissue-selective KCOs is highly desirable.At the molecular level, the K_ATP channel is an octameric complex, composed of two subunits: a pore-forming subunit of the Kir6.x subfamily and a sulfonylurea receptor (SUR). Different combinations of Kir6.x and SUR yield the tissue-specific K_ATP channel subtypes, which have different electrophysiological and pharmacological characters. It is generally accepted that Kir6.2/SUR1 constitutes the K_ATP channel of pancreatic β-cells and some neurons, whereas Kir6.2/SUR2A forms the K_ATP channel of cardiac and skeletal muscles. Kir6.2/SUR2B is the K_ATP isoform in nonvascular smooth muscles, whereas Kir6.1/SUR2B is the K_ATP channel subtype in vascular smooth muscles. The great diversity and complexity of K_ATP channels should facilitate the development of tissue-selective channel modulators.Iptakalim was designed and synthesized at our institute. It is a nonyl aliphatic secondary amine derivative, and its chemical structural characteristics differ from...