In vivo pharmacology of L-364,718, a new potent nonpeptide peripheral cholecystokinin antagonist.
The in vivo pharmacological activity of L-364,718, a new, potent peripheral cholecystokinin (CCK) antagonist, was characterized in several species using assay systems that measure various well known actions of CCK upon the gastrointestinal system. Administered p.o., L-364,178 was highly potent in antagonizing cholecystokinin octapeptide (CCK-8)-induced inhibition of gastric emptying in mice (ED50 = 38 micrograms/kg), rats (ED50 = 140 micrograms/kg) and dogs (ED50 = 91 micrograms/kg) as well as CCK-8-induced reduction in food consumption in rats (ED50 = 321 micrograms/kg). Administered i.v., L-364,718 effectively antagonized the contractile effects of CCK on the colon in rabbits (ED50 = 34 micrograms/kg) and the gallbladder in cats (ED50 = 210 micrograms/kg). Secretion of pancreatic protein and amylase elicited by CCK in cats was also antagonized by L-364,718 (ED50 less than 1.0 mg/kg i.v.). The CCK antagonism produced by L-364,718 in all species persisted for at least 2 to 5 hr. In the absence of exogenously administered CCK-8, L-364,718 per se had no effect in any of the assay systems studied, indicating a lack of CCK-like agonist properties. Specificity for CCK was demonstrated by the inability of L-364,718 (1.0-5.0 mg/kg) to antagonize either amino acid- or atropine-induced inhibition of gastric emptying in rats and dogs, respectively. L-364,718 also did not antagonize motilin-induced gallbladder contractions or secretin-induced pancreatic secretion in cats.(ABSTRACT TRUNCATED AT 250 WORDS)
D000681:Amylases / Q000378:metabolism; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D002415:Cats; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D003106:Colon / Q000187:drug effects; D020109:Devazepide; D004285:Dogs; D004435:Eating / Q000187:drug effects; D005260:Female; D005704:Gallbladder / Q000187:drug effects; D005746:Gastric Emptying / Q000187:drug effects; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D010191:Pancreatic Polypeptide / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012844:Sincalide / Q000037:antagonists & inhibitors
D001570:Benzodiazepinones; D010191:Pancreatic Polypeptide; D002766:Cholecystokinin; D000681:Amylases; D020109:Devazepide; D012844:Sincalide