The antisecretory effects of the
gastrin/
cholecystokinin-B (
CCK-B) receptor antagonist
YF476 ((R)-1-[2,3-dihydro-2-oxo-1-pivaloylmethyl-5-(2'-pyridyl) 1H-1,4-benzodiazepin-3-yl]-3-(3-methylaminophenyl)-
urea, CAS 155488-25-8) on
secretagogue- and
peptone-induced gastric acid secretion in beagle dogs with chronic
gastric fistula were examined. Plasma
gastrin concentrations were evaluated following introduction of
peptone into the stomach.
Intravenous administration of
YF476 dose-dependently inhibited
pentagastrin (1 microgram/kg/h)-induced gastric acid secretion, with an ED50 value of 0.0023 mumol/kg. In contrast,
intravenous administration of
YF476 (0.3 mumol/kg) did not affect
histamine (15 micrograms/kg/ h)-induced gastric acid secretion.
Oral administration of
YF476,
famotidine and
omeprazole dose-dependently inhibited
peptone (8%, 200 ml)-induced gastric acid secretion with ED50 values of 0.11, 0.76 and 4.28 mumol/kg, respectively. The antisecretory effect of
YF476 was about 7 and 40 times more potent than that of
famotidine and
omeprazole, respectively. Plasma
gastrin concentrations were increased by introduction of
peptone. These results suggest that
YF476 is an extremely potent and selective antisecretory
drug and the endogenous
gastrin plays an important role in
peptone-induced gastric acid secretion in dogs.