Functional proteins involved in regulation of intracellular Ca(2+) for drug development: pharmacology of SEA0400, a specific inhibitor of the Na(+)-Ca(2+) exchanger.

The Na(+)-Ca(2+) exchanger (NCX) is involved in regulation of intracellular Ca(2+) 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 Ca(2+) channels, Na(+) channels, K(+) channels, noradrenaline transporter, and 14 receptors; and it does not affect the activities of the store-operated Ca(2+) channel, Na(+)-H(+) exchanger, and several enzymes including Na(+),K(+)-ATPase and Ca(2+)-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.