NS1652

Description: NS1652 is a novel, reversible anion conductance inhibitor which blocks chloride channel with an IC50 of 1.6 uM in human and mouse red blood cells. In vitro application of NS1652 lowers the net KCl loss from deoxygenated sickle cells from about 12 mmol/L cells/h to about 4 mmol/L cells/h, a value similar to that observed in oxygenated cells. Experiments performed in mice demonstrate that NS1652 is well tolerated and decreases red cell anion conductance in vivo. A low cation conductance and a high anion conductance are characteristic of normal erythrocytes. In sickle cell anemia, the polymerization of hemoglobin S (HbS) under conditions of low oxygen tension is preceded by an increase in cation conductance. This increase in conductance is mediated in part through Ca(++)-activated K(+) channels. A net efflux of potassium chloride (KCl) leads to a decrease in intracellular volume, which in turn increases the rate of HbS polymerization. Treatments minimizing the passive transport of ions and solvent to prevent such volume depletion might include inhibitors targeting either the Ca(++)-activated K(+) channel or the anion conductance.

References: Blood. 2000 Mar 1; 95(5):1842-8.