Inhibitory Mechanism of SN-6, A Novel Benzyloxyphenyl Na+–Ca2+ Exchange Inhibitor

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We investigated the pharmacological properties of SN-6, a new selective Na+/Ca2+ exchanger (NCX) inhibitor. SN-6 preferentially inhibited the 45Ca2+ uptake via NCX compared with the 45Ca2+ efflux via NCX in NCX-transfected fibroblasts. SN-6 was three- to fivefold more inhibitory to the 45Ca2+ uptake via NCX1 (IC50 = 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.

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