Inhibitory mechanism of SN-6, a novel benzyloxyphenyl Na+/Ca2+ exchange inhibitor.
We investigated the pharmacological properties of SN-6, a new selective Na+/Ca2+ exchanger (NCX) inhibitor. SN-6 preferentially inhibited the (45)Ca2+ uptake via NCX compared with the (45)Ca2+ efflux via NCX in NCX-transfected fibroblasts. SN-6 was three- to fivefold more inhibitory to the (45)Ca2+ uptake via NCX1 (IC50 = 2.9 microM) than to that via NCX2 or NCX3. Our chimeric and site-directed mutagenesis 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.
Kita
Satomi
S
Department of Pharmacology, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
Iwamoto
Takahiro
T
D000818:Animals; D001593:Benzyl Compounds / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D018374:LLC-PK1 Cells; D016297:Mutagenesis, Site-Directed; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000235:genetics; D013552:Swine; D053778:Thiazolidines / Q000494:pharmacology*
C487681:2-(4-(4-nitrobenzyloxy)benzyl)thiazolidine-4-carboxylic acid ethyl ester; D001593:Benzyl Compounds; D019831:Sodium-Calcium Exchanger; D053778:Thiazolidines