title: YM022, a highly potent and selective CCKB antagonist inhibiting gastric acid secretion in the rat, the cat and isolated rabbit glands.
abstract: We investigated the effects of the novel CCKB/gastrin antagonist YM022 on gastric acid secretion in vivo and in vitro, compared to CI-988 and L365,260 as reference antagonists. In the anaesthetized rat, pentagastrin-induced stimulation of gastric acid secretion was dose-dependently and up to 100% inhibited by i.v. administration of YM022 with an ID50 of 0.009 +/- 0.0006 mumol/kg h in comparison to 0.6 +/- 0.03 and 3.40 +/- 0.05 mumol/kg h for CI-988 and L-365,260, respectively. In the gastric fistula cat, i.v. administration of YM022 produced a similar inhibitory effect with an ID50 of 0.02 mumol/kg in comparison to 1.6 and 2.5 mumol/kg for CI-988 and L-365,260, respectively. Furthermore, bolus injection of 0.6 mumol/kg YM022 produced 100% inhibition within 30 min and 85% inhibition was still observed after 3 h. In the isolated rabbit gastric glands, CCK8-stimulated 14C-aminopyrine uptake was inhibited according to the following rank order of potency: YM022 (IC50 = 0.0012 microM) > > CI-988 (IC50 = 0.2 microM) > > L365,260 (IC50 = 2.8 microM). Unlike with L365,260, no influence of CI-988 and YM022 on histamine-stimulated acid output was shown in this study. Thus, YM022 is a highly potent and selective gastric CCKB/gastrin receptor antagonist and has a long-lasting inhibitory effect on gastric acid secretion.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, INSERM, Unité 10, IFR02, Cellules Epithéliales, Hôpital Bichat, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Attoub
authors.forename: L
authors.initials: L
authors.lastname: Moizo
authors.forename: J P
authors.initials: JP
authors.lastname: Laigneau
authors.forename: B
authors.initials: B
authors.lastname: Alchepo
authors.forename: M J
authors.initials: MJ
authors.lastname: Lewin
authors.forename: A
authors.initials: A
authors.lastname: Bado
mesh_terms: D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D002415:Cats; D002766:Cholecystokinin / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005744:Gastric Acid / Q000378:metabolism*; D005747:Gastric Fistula / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D005755:Gastrins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*
chemical_list: D001570:Benzodiazepinones; D005755:Gastrins; D006727:Hormone Antagonists; D007211:Indoles; D010671:Phenylurea Compounds; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D000632:Aminopyrine; D001569:Benzodiazepines; C065599:PD 134308; C087260:YM 022; C058121:L 365260; D008536:Meglumine; D002766:Cholecystokinin