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

Abstract SR 27897 is a new non-peptide antagonist of CCK A receptors: 1-[[2-(4-(2-chlorophenyl)thiazol-2-yl)aminocarbonyl] indolyl] acetic acid. This compound is a potent ligand for CCK A binding sites (rat pancreatic membranes, K i = 0.2 nM) and is highly selective (CCK B and gastrin/CCK A IC 50 ratios of 800 and 5000 respectively). In vitro, it is competitive antagonist of cholecystokinin (CCK)-stimulated amylase release in isolated rat pancreatic acini (pA 2 = 7.50) and of CCK-induced guinea pig gall bladder contractions (pA 2 = 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 μg/kg (p.o.) it antagonized by 50% the CCK-induced inhibition of gastric emptying of a charcoal meal in mice, and 72 μg/kg (p.o.) was the median effective dose for inhibiting CCK-induced gall bladder emptying in mice. SR 27897 was also very active (ED 50 = 27 μ g/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 CCK A receptors, is highly potent in animal models whatever the route of administration and has a long duration of action. Thus this compound may be useful for studying the physiological or pathological role of CCK in humans.