Effects of YF476, a potent and selective gastrin/cholecystokinin-B receptor antagonist, on gastric acid secretion in beagle dogs with gastric fistula.
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.
Takemoto
Y
Y
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., Tsukuba, Japan.
Yuki
H
H
Nishida
A
A
Ito
H
H
Kobayashi-Uchida
A
A
Takinami
Y
Y
Akuzawa
S
S
Ohta
M
M
Satoh
M
M
Semple
G
G
Miyata
K
K
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D004285:Dogs; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D005755:Gastrins / Q000097:blood; D006632:Histamine / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology*; D008297:Male; D010418:Pentagastrin / Q000494:pharmacology; D010461:Peptones / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*
D001570:Benzodiazepinones; D005755:Gastrins; D006727:Hormone Antagonists; D010461:Peptones; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; D006632:Histamine; D010418:Pentagastrin; C104428:YF 476