We evaluated the effect of
YM022 [(R)-1-[2,3-dihydro-1-(2'- methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3- (3-methylphenyl)
urea], a potent and selective
gastrin/
cholecystokinin-B receptor antagonist, on gastric acid secretion and gastric and duodenal lesions in rats. Oral
YM022 (0.1-10 mumol/kg),
famotidine (0.3-30 mumol/kg) and
omeprazole (3-100 mumol/kg) dose-dependently suppressed
acid secretion in pylorusligated rats with ED50 values of 0.83, 1.63 and 10.9 mumol/kg, respectively.
YM022 (1-10 mumol/kg p.o.),
famotidine (1-10 mumol/kg p.o.) and
omeprazole (10-100 mumol/kg p.o.) prevented
indomethacin-induced gastric lesions in a dose-related manner. The potency of
YM022 was comparable to that of
famotidine and was 8 times greater than that of
omeprazole.
YM022 and
famotidine partially inhibited gastric damage induced by water-immersion and restraint stress, whereas
omeprazole abolished these lesions. In an acidified
ethanol-induced gastric injury model, all three drugs inhibited the formation of erosions. The
YM022 dosage required in this model was much greater than that required in the inhibition of gastric acid. The inhibitory effect of
YM022 was partially reversed by
indomethacin, indicating the involvement of a
prostaglandin-mediated pathway.
YM022 (3-100 mumol/kg p.o.),
famotidine (1-30 mumol/kg p.o.) and
omeprazole (3-100 mumol/kg p.o.) inhibited
mepirizole-induced
duodenal ulcers. On the basis of ED50 values,
YM022 was 5 times less potent than
famotidine and as potent as
omeprazole against
mepirizole-induced
duodenal ulcers. These results suggest that
YM022 possesses antisecretory and antiulcer activities that are as potent as those of
famotidine in rats and that
YM022 represents a useful therapeutic agent in the treatment of
peptic ulcer disease.