Studies on the mechanism of action of the gastric microsomal (H+ + K+)-ATPase inhibitors SCH 32651 and SCH 28080.
The novel antisecretory agents SCH 32651 and SCH 28080 were evaluated for their antisecretory activities in vitro as well as for their abilities to inhibit the (H+ + K+)-ATPase enzyme activity in preparations of microsomal membranes from rabbit fundic mucosa. SCH 32651 and SCH 28080 inhibited both the histamine- and dibutyryl cAMP-stimulated uptake of [14C]-aminopyrine into isolated parietal cells with IC50 values of about 1.5 and 0.02 microM respectively. SCH 32651 and SCH 28080 competitively inhibited the K+-stimulated hydrolysis of ATP catalyzed by the (H+ + K+)-ATPase with Ki values of 16.3 and 0.12 microM respectively. The inhibition of the enzyme by both compounds was not affected by the addition of the sulfhydryl reducing agents dithiothreitol or beta-mercaptoethanol, was readily reversible by dilution or washing, and was dependent upon the concentration of KCl used to stimulate the enzyme. These data suggest that SCH 32651 and SCH 28080 are reversible, competitive inhibitors of the K+-stimulated hydrolysis of ATP.
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D005753:Gastric Mucosa / Q000201:enzymology / Q000648:ultrastructure*; D017506:H(+)-K(+)-Exchanging ATPase; D006632:Histamine / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D008623:Mercaptoethanol / Q000494:pharmacology; D008861:Microsomes / Q000201:enzymology; D009853:Omeprazole / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D011817:Rabbits
D007093:Imidazoles; D011719:Pyrazines; C035235:Sch 28080; D000632:Aminopyrine; D008623:Mercaptoethanol; D003994:Bucladesine; D006632:Histamine; C042837:3-amino-2-methyl-8-phenylmethoxyimidazo(1,2-a)pyrazine; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase; D009853:Omeprazole; D004229:Dithiothreitol