Inhibition of gastric H+/K+-ATPase by substituted imidazo[1,2-a]pyridines.
A hydrophobic imidazopyridine, SCH 28080 (3-cyanomethyl-2-methyl-8-phenylmethoxy)imidazo[1,2-a]pyridine) has previously been shown to inhibit gastric acid secretion in vivo and in vitro. Studies of isolated gastric H+/K+-ATPase have demonstrated that SCH 28080 reversibly inhibited the enzyme and competitively interacted with the K+-stimulated ATPase and p-nitrophenylphosphatase activities of the H+/K+-ATPase. To elucidate the mechanism of inhibition further, for example to establish whether the inhibitor interaction occurs on the luminal or the cytosolic side of the enzyme or if compound pKa influences inhibition, SCH 28080 and three analogues have been studied. We have examined the effects on K+-stimulated ATPase activity in isolated ion-permeable membrane vesicles at different pH values and KCl concentrations. In ion-tight membrane fractions the effect on acid formation was estimated. The results are in agreement with the hypothesis that the protonated, and thus positively charged, form of SCH 28080 is the active species, and that the inhibitory effect is exerted by binding of the compound to the luminal side of the H+/K+-ATPase.
Briving
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Hässle Gastrointestinal Research Laboratories, Department of Biology, Mölndal, Sweden.
Andersson
B M
BM
Nordberg
P
P
Wallmark
B
B
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D005750:Gastric Juice / Q000378:metabolism; D017506:H(+)-K(+)-Exchanging ATPase; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D013270:Stomach / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013552:Swine
D007093:Imidazoles; C035235:Sch 28080; D000632:Aminopyrine; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase