Neuropharmacological Mechanisms Of Iptakalim Hydrochloride, A Novel ATP-sensitive Potassium Channel Opener

ATP-sensitive potassium channel (K_ATP) widely expressed in many tissue and cell types including neurons are heteromultimers of sulfonylurea receptor (SUR) and inwardly rectifying potassium channel subunits (Kir6.x) associated with 1:1 stoichiometry as a tetramer (SUR/Kir6.x)₄. Neuronal K_ATP channels are involved in the mediation of cellular excitability sensing and metabolic status. Under physiological condition, K_ATP are mostly maintained in the close state, but they possess important pathophysiological functions in acute brain ischemic and chronic neurodegenerative diseases. Some K_ATP openers have been reported to be effective in preclinical experiments. However, they lack clinical effectiveness, mainly because of strong detrimental side effects or poor brain penetration. We hypothesized that the development of K_ATP channel openers with low toxicity and brain-blood barrel permeable characteristics would be effective for stroke therapy. We have designed and synthesized thousands of compounds and have finally screened out the most promising candidate, Iptakalim hydrochloride (Ipt). Ipt is...