Peripheral biological activity of SR 27897 : a new potent non-peptide antagonist of CCKA receptors

• Published in: European journal of pharmacology Vol. 232; no. 1; pp. 13 - 19
• Main Authors: GULLY, D, FREHEL, D, MARCY, C, SPINAZZE, A, LESPY, L, NELIAT, G, MAFFRAND, J.-P, LE FUR, G
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 23.02.1993
• Subjects: Administration, Oral; Amylases - drug effects; Animals; Benzodiazepinones - pharmacology; Binding, Competitive; Biological and medical sciences; Cholecystokinin - antagonists & inhibitors; Cholecystokinin - metabolism; Devazepide; Digestive system; Dose-Response Relationship, Drug; Female; Gallbladder - drug effects; Gastric Emptying - drug effects; Gastrins - drug effects; Guinea Pigs; In Vitro Techniques; Indoleacetic Acids - pharmacology; Injections, Intravenous; Male; Medical sciences; Mice; Pancreas - drug effects; Pharmacology. Drug treatments; Radioligand Assay; Rats; Rats, Wistar; Receptors, Cholecystokinin - antagonists & inhibitors; Stomach - drug effects; Thiazoles - pharmacology; Amylase; Rat; Enzyme; Digestive system; Rodentia; Peptide hormone; Gastric emptying; Neuropeptide; Biological activity; Cholecystokinin receptor A; Vertebrata; Mammalia; Guinea pig; Gastrointestinal hormone; Animal; Gallbladder; Antagonist; Cholecystokinin; Release; Hormonal receptor
• ISSN: 0014-2999
• DOI: 10.1016/0014-2999(93)90722-t

SR 27897 is a new non-peptide antagonist of CCKA receptors: 1-[[2-(4-(2-chlorophenyl)thiazol-2-yl)aminocarbonyl] indolyl] acetic acid. This compound is a potent ligand for CCKA binding sites (rat pancreatic membranes, Ki = 0.2 nM) and is highly selective (CCKB and gastrin/CCKA IC50 ratios of 800 and 5000 respectively). In vitro, it is a competitive antagonist of cholecystokinin (CCK)-stimulated amylase release in isolated rat pancreatic acini (pA2 = 7.50) and of CCK-induced guinea pig gall bladder contractions (pA2 = 9.57). In in vivo gastrointestinal models, SR 27897 confirmed the potency obtained in vitro: at 1 mg/kg (i.v.) it completely reversed the CCK-induced amylase secretion, at 3 micrograms/kg (p.o.) it antagonized by 50% the CCK-induced inhibition of gastric emptying of a charcoal meal in mice, and 72 micrograms/kg (p.o.) was the median effective dose for inhibiting CCK-induced gall bladder emptying in mice. SR 27897 was also very active (ED50 = 27 micrograms/kg p.o.) in the gall bladder emptying protocol with egg yolk as an inducer of endogenous CCK release. SR 27897 had a long-lasting action in all the experiments, with no differences between oral and intravenous routes of administration. SR 27897 was more or less effective than L-364,718, depending on the model and the species. Both compounds increased the gall bladder volume of fasting mice, but the effect of SR 27897 was 10 times lower than that of L-364,718. In summary, SR 27897 is a selective antagonist of CCKA receptors, is highly potent in animal models whatever the route of administration and has a long duration of action.