Inhibitory Mechanism of SN-6, A Novel Benzyloxyphenyl Na~+/Ca~(2+) Exchange Inhibitor

摘要

We investigated the pharmacological properties of SN-6, a new selective Na~+/Ca~(2+) exchanger (NCX) inhibitor. SN-6 preferentially inhibited the ~(45)Ca~(2+) uptake via NCX compared with the ~(45)Ca~(2+) efflux via NCX in NCX-transfected fibroblasts. SN-6 was three- to fivefold more inhibitory to the ~(45)Ca~(2+) uptake via NCX1 (IC_(50) = 2.9 μM) than to that via NCX2 or NCX3. Our chimeric and site-directed mutageneses revealed that Phe-213, Val-227, Tyr-228, Gly-833, and Asn-839 in NCX1 are molecular determinants for interaction with SN-6. We also found that SN-6 potently protects against hypoxia/reoxygenation-induced cell damage in renal tubular cells.