title: Characterization of antisecretory and antiulcer activity of CR 2945, a new potent and selective gastrin/CCK(B) receptor antagonist.
abstract: The antigastrinic, antisecretory and antiulcer activities of CR 2945, (R)-1-naphthalenepropanoic acid,beta-[2-[[2-(8-azaspiro[4.5]dec-8-yl-carbonyl)-4,6-dimethylph enyl] amino]-2-oxoethyl], were investigated in vitro and in vivo in rats and cats. Its activities were compared with those of two gastrin/CCK(B) receptor antagonists, L-365,260 (3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin -3-yl)-N'-(3-methylphenyl)urea and CAM-1028 (4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[1,7,7-trimethylbicyclo [2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino -4-oxo-[1S-1alpha,2beta[S'(S')4alpha]]-butanoate -N-methyl-D-glucamine), of the histamine H2 receptor antagonist, ranitidine, and the proton pump inhibitor, omeprazole. Cytosolic Ca2+ elevation in rabbit parietal cells induced by gastrin (50 nM) was blocked by CR 2945 with an IC50 value of 5.9 nM. CAM-1028 and L-365,260 showed similar activity. CR 2945 antagonized pentagastrin-stimulated gastric acid secretion in rats (ED50 = 1.3 mg kg(-1) i.v. and 2.7 mg kg(-1) i.d.) and cats (1.6 mg kg(-1) i.v.). CR 2945 was slightly less potent than the reference compounds after i.v. administration, whereas after intraduodenal (i.d.) administration, it was more potent than both ranitidine and omeprazole. In the rat, the gastrin antagonism exhibited by CR 2945 was reversible and competitive, with a pA2 value of 7.33. CR 2945 had specific antigastrin activity, as it was unable to antagonize the gastric acid secretion stimulated by histamine or carbachol in rats up to the dose of 30 mg kg(-1). CR 2945 was about as efficacious as ranitidine against the indomethacin- and ethanol-induced gastric ulcers and the cysteamine-induced duodenal ulcer in rats. On the contrary, L-365,260 was only slightly effective. These results suggest that CR 2945 might be a promising compound for the therapy of acid-related disorders, and that its clinical use could help clarify the therapeutic potential of gastrin/CCK(B) receptor antagonists in the gut.
authors: Rotta Research Laboratorium, Monza (MI), Italy. Laura_Radaelli@rotta.com
authors: F
authors: F
authors: Makovec
authors: L
authors: L
authors: Revel
authors: O
authors: O
authors: Letari
authors: L
authors: L
authors: Mennuni
authors: M
authors: M
authors: Impicciatore
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002415:Cats; D002908:Chronic Disease; D003543:Cysteamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism*; D005747:Gastric Fistula / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D005755:Gastrins / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009853:Omeprazole / Q000494:pharmacology; D010295:Parietal Cells, Gastric / Q000187:drug effects / Q000378:metabolism; D010418:Pentagastrin / Q000494:pharmacology; D010477:Perfusion; D010671:Phenylurea Compounds / Q000494:pharmacology; D011817:Rabbits; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013270:Stomach / Q000187:drug effects; D013276:Stomach Ulcer / Q000139:chemically induced / Q000517:prevention & control
chemical_list: D014151:Anti-Anxiety Agents; D000897:Anti-Ulcer Agents; D001570:Benzodiazepinones; C116183:CR 2945; D005755:Gastrins; D006635:Histamine H2 Antagonists; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines; C058121:L 365260; D000431:Ethanol; D003543:Cysteamine; D011899:Ranitidine; D010418:Pentagastrin; D009853:Omeprazole; D002118:Calcium; D007213:Indomethacin