ME-3407, a new antiulcer agent, inhibits acid secretion by interfering with redistribution of H(+)-K(+)-ATPase.
ME-3407 is a newly developed antiulcer drug that markedly promoted the healing of acetic acid-induced chronic ulcers in rats presumably due to potent inhibition of acid secretion. ME-3407 and its metabolites, the sulfoxide of which was preserved, produced dosedependent inhibition of aminopyrine accumulation by rabbit gastric glands stimulated by any agonist, suggesting that the site of their action was downstream from the production of second messengers. Although one of the metabolites, EF-4025, showed some inhibitory effects on functional activities of H(+)-K(+)-ATPase, ME-3407 itself was not a proton pump inhibitor. ME-3407, but not omeprazole, inhibited the stimulation-associated redistribution of H(+)-K(+)-ATPase from microsomes into the apical membranes in addition to delocalizing ezrin, a putative F-actin-membrane linker, from apical plasma membrane. ME-3407 and EF-4025 inhibited myosin light chain kinase (MLCK) and protein kinase A activities. Because another MLCK inhibitor, wortmannin, showed the same properties as ME-3407, i.e., inhibition of aminopyrine accumulation, inhibition of stimulation-associated redistribution of H(+)-K(+)-ATPase, and abnormal distribution of ezrin, we hypothesize that MLCK is one of the potential targets for the drug. We conclude that ME-3407 is a promising drug for treating peptic ulcers, as well as a useful tool for studying mechanisms of parietal cell activation, especially related to the recruitment and recycling of the proton pump.
Urushidani
T
T
Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Muto
Y
Y
Nagao
T
T
Yao
X
X
Forte
J G
JG
D019342:Acetic Acid; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism*; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors; D054328:Proton Pump Inhibitors; D017494:Proton Pumps / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced / Q000503:physiopathology; D013844:Thiazoles / Q000494:pharmacology*; D014018:Tissue Distribution; D000077191:Wortmannin; D014945:Wound Healing / Q000187:drug effects
D000730:Androstadienes; D000897:Anti-Ulcer Agents; C106474:EF 4025; D004791:Enzyme Inhibitors; C106473:ME 3407; D054328:Proton Pump Inhibitors; D017494:Proton Pumps; D011725:Pyridines; D013844:Thiazoles; D017868:Cyclic AMP-Dependent Protein Kinases; D009219:Myosin-Light-Chain Kinase; D017506:H(+)-K(+)-Exchanging ATPase; D019342:Acetic Acid; D000077191:Wortmannin