YM022, a highly potent and selective CCKB antagonist inhibiting gastric acid secretion in the rat, the cat and isolated rabbit glands

Summary— We investigated the effects of the novel CCK_B/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 iv administration of YM022 with an ID₅₀ of 0.009 ± 0.0006 μmol/kg h in comparison to 0.6 ± 0.03 and 3.40 ± 0.05 μmol/kg h for CI-988 and L-365,260, respectively. In the gastric fistula cat, iv administration of YM022 produced a similar inhibitory effect with an ID₅₀ of 0.02 μmol/kg in comparison to 1.6 and 2.5 μmol/kg for CI-988 and L-365,260, respectively. Furthermore, bolus injection of 0.6 μmol/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 μM) ≫ CI-988 (IC₅₀ = 0.2 μM) ≫ L365.260 (IC₅₀ = 2.8 μM). 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 CCK₈/gastrin receptor antagonist and has a long-lasting inhibitory effect on gastric acid secretion.