Biochemical properties of a newly synthesized H(+)/K(+) ATPase inhibitor, 1-(2-methyl-4-methoxyphenyl)-4-.
A new compound, 1-(2-methyl-4-methoxyphenyl)-4-[(3-hydroxypropyl)amino]-6-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (DBM-819), inhibited gastric H(+)/K(+) ATPase in the rabbit (EC 3.6.1.3) with an IC(50) value of 5 microM. However, DBM-819 was a weak inhibitor of kidney Na(+)/K(+) ATPase in the dog, indicating that it has selectivity for the gastric H(+)/K(+) ATPase. The inhibition was reversible and non-competitive with respect to the activating cation K(+). The presence of dithiothreitol did not protect the H(+)/K(+) ATPase from inactivation. The inhibition by DBM-819 was potentiated by acid pretreatment of the compound, suggesting that DBM-819 is converted into a more active intermediate under acidic conditions. The results suggest that DBM-819 is a potent, selective and reversible inhibitor of gastric H(+)/K(+) ATPase, and that the essential cysteine residue may not be involved in the DBM-819-mediated inactivation of gastric H(+)/K(+) ATPase.
Cheon
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Pharmaceutical Screening Center, Korea Research Institute of Chemical Technology, 100 Jang-Dong, Yusong-Gu, 305-343, Taejon, South Korea. hgcheon@pado.krict.re.kr
Lim
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Lee
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D000143:Acids / Q000494:pharmacology; D000818:Animals; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009853:Omeprazole / Q000494:pharmacology; D054328:Proton Pump Inhibitors; D011758:Pyrroles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D011817:Rabbits
D000143:Acids; C419624:DBM-819; D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; D011758:Pyrroles; D011804:Quinolines; D017506:H(+)-K(+)-Exchanging ATPase; D009853:Omeprazole; D004229:Dithiothreitol