YM022 H-1,4-BENZODIAZEPIN-3-YL]-3-(3-METHYLPHENYL)UREA), A POTENT ANDSELECTIVE GASTRIN CHOLECYSTOKININ-B RECEPTOR ANTAGONIST, PREVENTS GASTRIC AND DUODENAL LESIONS IN RATS

We evaluated the effect of YM022 2,3-dihydro-1-(2'-methylphenacyl)-2-o xo-5-phenyl-1 H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea}, a pot ent and selective gastrin/cholecystokinin-B receptor antagonist, on ga stric acid secretion and gastric and duodenal lesions in rats. Oral YM 022 (0.1-10 mu mol/ kg), famotidine (0.3-30 mu mol/kg) and omeprazole (3-100 mu mol/ kg) dose-dependently suppressed acid secretion in pylor us-ligated rats with ED(50) values of 0.83, 1.63 and 10.9 mu mol/kg, r espectively. YM022 (1-10 mu mol/kg p.o.), famotidine (1-10 mu mol/ kg p.o.) and omeprazole (10-100 mu mol/kg p.o.) prevented indomethacin-in duced gastric lesions in a dose-related manner. The potency of YM022 w as 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 a bolished 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 par tially reversed by indomethacin, indicating the involvement of a prost aglandin-mediated pathway. YM022 (3-100 mu mol/kg p.o.), famotidine (1 -30 mu mol/kg p.o.) and omeprazole (3-100 mu mol/kg p.o.) inhibited me pirizole-induced duodenal ulcers. On the basis of ED(50) values, YM022 was 5 times less potent than famotidine and as potent as omeprazole a gainst mepirizole-induced duodenal ulcers. These results suggest that YM022 possesses antisecretory and antiulcer activities that are as pot ent as those of famotidine in rats and that YM022 represents a useful therapeutic agent in the treatment of peptic ulcer disease.