YM022, A HIGHLY POTENT AND SELECTIVE CCKB ANTAGONIST INHIBITING GASTRIC-ACID SECRETION IN THE RAT, THE CAT AND ISOLATED RABBIT GLANDS

We investigated the effects of the novel CCKB/gastrin antagonist YM022 on gastric acid secretion in vivo and in vitro, compared to CI-988 an d L365,260 as reference antagonists. In the anaesthetized raf pentagas trin-induced stimulation of gastric acid secretion was dose-dependentl y and up to 100% inhibited by iv administration of YM022 with an ID50 of 0.009 +/- 0.0006 mu mol/kg h in comparison to 0.6 +/- 0.03 and 3.40 +/- 0.05 mu mol/kg h for CI-988 and L-365,260, respectively, In the g astric fistula cat, iv administration of YM022 produced a similar inhi bitory effect with an ID50 of 0.02 mu mol/kg in comparison to 1.6 and 2.5 mu mol/kg for CI-988 and L-365,260, respectively. Furthermore, bol us injection of 0.6 mu mol/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 C-14-aminopyrine uptake was inh ibited according to the following rank order of potency: YM022 (IC50 = 0.0012 mu M) >> CI-988 (IC50 = 0.2 mu M) >> L365,260 (IC50 = 2.8 mu M ). 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 high ly potent and selective gastric CCKB/gastrin receptor antagonist and h as a long-lasting inhibitory effect on gastric acid secretion. (C) 199 8 Elsevier, Paris.