Peripheral biological activity of SR 27897: a new potent non-peptide antagonist of CCKA receptors.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Gully
D
D
Exploratory Research Department, Sanofi Recherche, Toulouse, France.
Fréhel
D
D
Marcy
C
C
Spinazzé
A
A
Lespy
L
L
Neliat
G
G
Maffrand
J P
JP
Le Fur
G
G
D000284:Administration, Oral; D000681:Amylases / Q000187:drug effects; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D001667:Binding, Competitive; D002766:Cholecystokinin / Q000037:antagonists & inhibitors / Q000378:metabolism; D020109:Devazepide; D004305:Dose-Response Relationship, Drug; D005260:Female; D005704:Gallbladder / Q000187:drug effects; D005746:Gastric Emptying / Q000187:drug effects; D005755:Gastrins / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007210:Indoleacetic Acids / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D010179:Pancreas / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013270:Stomach / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*
D001570:Benzodiazepinones; D005755:Gastrins; D007210:Indoleacetic Acids; D011949:Receptors, Cholecystokinin; D013844:Thiazoles; C080460:SR 27897; D002766:Cholecystokinin; D000681:Amylases; D020109:Devazepide