Characterization of antisecretory and antiulcer activity of CR 2945, a newpotent and selective gastrin/CCKB receptor antagonist

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-dimethylphenyl] amino]-2-oxoethyl], were investigated in vitro and in vi vo in rats and cats. Its activities were compared with those of two gastrin /CCKB 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-(1 H-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-1 alpha,2 beta[S'(S')4 alpha]]-butanoate-N-methyl-D-glucamine), of the hista mine H-2 receptor antagonist, ranitidine, and the proton pump inhibitor, om eprazole. Cytosolic Ca2+ elevation in rabbit parietal cells induced by gast rin (50 nM) was blocked by CR 2945 with an IC50 value of 5.9 nM. CAM-1028 a nd L-365,260 showed similar activity. CR 2945 antagonized pentagastrin-stim ulated 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 pote nt than the reference compounds after i.v. administration, whereas after in traduodenal (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 pA(2) value of 7.33. CR 2945 had specif ic antigastrin activity, as it was unable to antagonize the gastric acid se cretion stimulated by histamine or carbachol in rats up to the dose of 30 m g kg(-1). CR 2945 was about as efficacious as ranitidine against the indome thacin- and ethanol-induced gastric ulcers and the cysteamine-induced duode nal 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 th erapy of acid-related disorders, and that its clinical use could help clari fy the therapeutic potential of gastrin/CCKB receptor antagonists in the gu t. (C) 1999 Elsevier Science B.V. All rights reserved.