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.
Matsuda
Toshio
T
Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka. matsuda@phs.osaka-u.ac.jp
Koyama
Yutaka
Y
Baba
Akemichi
A
D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015195:Drug Design; D008954:Models, Biological; D015394:Molecular Structure; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control; D010647:Phenyl Ethers / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*
D000814:Aniline Compounds; D010647:Phenyl Ethers; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger; D002118:Calcium