title: Evaluation of the specificity and potency of a series of cholecystokinin-B/gastrin receptor antagonists in vivo.
abstract: The potency and specificity of five proposed cholecystokinin-B receptor antagonists, YM022, RP73870, L-740,093, L-365,260 and LY288513, were studied in rats and mice. Gastrin activates rat stomach histidine decarboxylase via cholecystokinin-B/gastrin receptors. To examine cholecystokinin-B receptor-mediated effects of the five drugs, they were infused intravenously to fasted rats and the histidine decarboxylase activity in the oxyntic mucosa was determined. While YM022, RP73870, L-740,093 and L-365,260 failed to activate histidine decarboxylase, they dose-dependently antagonized the gastrin-induced histidine decarboxylase activation. LY288513 had no effect in the doses tested. The maximal inhibitory effect of L-365,260, L-740,093, RP73870 and YM022 on histidine decarboxylase, activated by the intravenous infusion of an ED50 does of gastrin (0.4 nmoles/kg/hr), was seen at doses of 3, 0.3, 0.1 and 0.1 mumoles/kg/hr, respectively; the corresponding ID50 values were 0.4, 0.02, 0.007 and 0.004 mumoles/kg/h. In a follow-up study, YM022 and RP73870 were found to produce a rightward shift of the gastrin dose-response curve, which is consistent with competitive inhibition. The effect of the five drugs on a cholecystokinin-A receptor-mediated response was examined by studying gastric emptying in mice. Cholecystokinin-8s, given by a subcutaneous bolus injection, dose-dependently inhibits gastric emptying. The specific cholecystokinin-A receptor antagonist devazepide (given intravenously as a bolus injection) antagonized the effect of cholecystokinin-8s in a dose-dependent manner, with an ID50 value of 28 nmoles/kg. None of the drugs inhibited the gastric emptying or prevented the cholecystokinin-8s-induced effect at the doses tested. The results indicate that YM022, RP73870, L-740,093 and L-365,260 act as cholecystokinin-B receptor antagonists in vivo, being without measurable agonistic activity. Furthermore, they do not interact with cholecystokinin-A receptors at te doses tested. Among the cholecystokinin-B receptor antagonists studied YM022 and RP73870 are superior, the rank order of potency being YM022 > or = RP73870 > L-740,093 > L-365,260.
authors.affiliation: Department of Pharmacology, University of Lund, Sweden.
authors.forename: X Q
authors.initials: XQ
authors.lastname: Ding
authors.forename: R
authors.initials: R
authors.lastname: Håkanson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology; D001570:Benzodiazepinones / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology; D006640:Histidine Decarboxylase / Q000378:metabolism; D006727:Hormone Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007262:Infusions, Intravenous; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000897:Anti-Ulcer Agents; D001570:Benzodiazepinones; D006727:Hormone Antagonists; D010671:Phenylurea Compounds; D011720:Pyrazoles; C094193:RP 73870; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines; C074681:1-(4-bromophenylaminocarbonyl)-4,5-diphenyl-3-pyrazolidinone; C087260:YM 022; C090649:L 740093; C058121:L 365260; D006640:Histidine Decarboxylase