YM022, a highly potent and selective CCK_B 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.

Retracted: Serotonin and cholecystokinin synergistically stimulate rat vagal primary afferent neurones

“…In the anaesthetized rat, L‐365 260 dose‐dependently inhibited pentagastrin‐induced stimulation of gastric acid secretion, with an ID 50 of 2.5 μmol kg −1 h −1 (Attoub et al 1998). Vagal nodose neuronal responses to CCK were monitored as previously described.…”

Pharmacological and molecular characterization of muscular cholecystokinin receptors in the human lower oesophageal sphincter

“…The structurally related benzodiazepines L‐365 260 and YM022 are selective antagonists for the human CCK‐B receptor subtype; L‐365 260 is a competitive antagonist, and YM022 behaves as an irreversible antagonist. YM022 has shown a higher potency than that of L‐365 260 in several animal bioassays (IC 50 0.0012 μmol L –1 and 2.8 μmol L –1 , respectively), 30 and a selectivity for CCK‐B/gastrin receptors 1000‐fold greater than for the CCK‐A receptor, 31 , 32 whereas the selectivity of L‐365 260 for the CCK‐B receptor was two orders of magnitude higher than for the CCK‐A receptor 29 . YM022 has shown a IC 50 of 7.4 nmol L –1 on a bioassay using the human CCK‐B receptor expressed in CHO cells, 33 and showed a selectivity for the human CCK‐B receptor 6000‐fold greater than the A type 34 .…”

Gastrin and D 1 Dopamine Receptor Interact to Induce Natriuresis and Diuresis

“…However, sulfated CCK octapeptide has a much greater affinity to CCK A R than CCK B R while gastrin has a much greater affinity to CCK B R than CCK A R 20 . Indeed, the natriuretic and diuretic effects of gastrin were blocked by the selective CCK B R antagonist, CI-988 26,37 . While CCK B R is expressed in the renal proximal tubule 24,25 , CCK A R is not 38 .…”

“…We hypothesized, further, that this interaction is impaired in hypertension. To test these hypotheses, we studied the natriuretic effect of intrarenal arterial infusion of gastrin with or without co-infusion of a D 1 -like receptor agonist, fenoldopam, in the presence or absence of their respective antagonists, CI-988 (CCK B R antagonist) 26 and SCH23390 27,28 , D 1 -like receptor antagonist, in the normotensive Wistar-Kyoto (WKY) rat and the spontaneously hypertensive rat (SHR). We also studied the colocalization and physical and functional interactions between CCK B R and D 1 R in rat RPT cells.…”