Functional Proteins Involved in Regulation of Intracellular Ca²⁺ for Drug Development:
Pharmacology of SEA0400, a Specific Inhibitor of the Na⁺-Ca²⁺ Exchanger

Abstract

The Na⁺-Ca²⁺ exchanger (NCX) is involved in regulation of intracellular Ca²⁺ concentration. A specific inhibitor of NCX has been required for clarification of the physiological and pathological roles of NCX. We have developed 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a highly potent and selective inhibitor of NCX. SEA0400 in the concentration range that inhibits NCX exhibits negligible affinities for the Ca²⁺ channels, Na⁺ channels, K⁺ channels, noradrenaline transporter, and 14 receptors; and it does not affect the activities of the store-operated Ca²⁺ channel, Na⁺-H⁺ exchanger, and several enzymes including Na⁺,K⁺-ATPase and Ca²⁺-ATPase. Furthermore, recent studies show that SEA0400 attenuates ischemia-reperfusion injury in the brain, heart, and kidney and radiofrequency lesion-induced edema in rat brain. These findings suggest that NCX plays a key role in ischemia-reperfusion injury and may be a target molecule for treatment of reperfusion injury-related diseases.