SELECTIVE MAXI-K- POTASSIUM CHANNEL OPENERS FUNCTIONAL UNDER CONDITIONS OF HIGH INTRACELLULAR CALCIUM CONCENTRATION, METHODS AND USES THEREOF

摘要

The present invention describes calcium sensitive and selective maxi-Kpotassium channel opener/activator compounds that function to open maxi-Kchannels under conditions of high intracellular calcium concentrations, andwhich do not significantly affect the opening of maxi-K channel proteins underconditions of low or physiologically normal intracellular calciumconcentrations. Methods of assaying for and using such compounds are alsoprovided. According to the invention, whole cell voltage patch-clamp studiesnewly demonstrated that the ability of opener compounds, e.g., fluoro-oxindoles and chloro-oxindoles, to open maxi-K channels was sensitive to theintracellular ca2+ concentration ([Ca2+])i, i.e. more channels opened at morenegative potentials. Particular fluoro-oxindole and chloro-oxindole compoundsproduced significant increases in whole-cell maxi-K potassium channel-mediatedoutward currently only in cells having higher [Ca2+]i, compared with effectsin lower [Ca2+]i. Such compounds provide Ca2+-sensitive and selective openersof maxi-K channels which show maximum effectiveness under conditions ofincreased [Ca2+]i and, as such, provide treatments for diseases and disordersin which cells undergo, or are subject to, traumatic stress due to highinternal calcium levels, such as stroke.