S3226, a novel inhibitor of Na+/H+ exchanger subtype 3 in various cell types.
Inhibition of Na+/H+ exchange (NHE) subtypes has been investigated in a study of the mouse fibroblast L cell line (LAP1) transfected with human (h) NHE1, rabbit (rb) NHE2, rat (rt) or human (h) NHE3 as well as an opossum kidney cell line (OK) and porcine renal brush-border membrane vesicles (BBMV). S3226 ¿3-[2-(3-guanidino-2-methyl-3-oxo-propenyl)-5-methyl-phenyl]-N-isopro pylidene-2-methyl-acrylamide dihydro-chloride¿ was the most potent and specific NHE3 inhibitor with an IC50 value of 0.02 micromol/l for the human isoform, whereas its IC50 value for hNHE1 and rbNHE2 was 3.6 and approximately = 80 micromol/l, respectively. In contrast, amiloride is a weak NHE3 inhibitor (IC50>100 micromol/l) with a higher affinity to hNHE1 and rbNHE2. Cariporide (4-isopropyl-3-methylsulphonyl-benzoyl-guanidine methane-sulphonate), which has an IC50 for NHE3 of approximately 1 mmol/l, is a highly selective NHE1 inhibitor (0.08 micromol/l). Therefore, S3226 is a novel tool with which to investigate the physiological and pathophysiological roles of NHE3 in animal models.
Schwark
J R
JR
Hoechst AG, Hoechst Marion Roussel, H 821, D-65926 Frankfurt am Main, Germany.
Jansen
H W
HW
Lang
H J
HJ
Krick
W
W
Burckhardt
G
G
Hropot
M
M
D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors; D008689:Methacrylates / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008871:Microvilli / Q000187:drug effects; D009893:Opossums; D011817:Rabbits; D051381:Rats; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013450:Sulfones / Q000494:pharmacology; D013552:Swine
C118956:3-(2-(3-guanidino-2-methyl-3-oxo-propenyl)-5-methylphenyl)-N-isopropylidene-2-methyl-acrylamide dihydrochloride; D006146:Guanidines; D007473:Ion Channels; D008689:Methacrylates; C081517:SLC9A2 protein, human; C000613385:SLC9A3 protein, human; C513111:Slc9a2 protein, mouse; C513110:Slc9a2 protein, rat; C000613386:Slc9a3 protein, mouse; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C069139:growth factor-activatable Na-H exchanger NHE-1; D000584:Amiloride; C093373:cariporide