Evaluation of the Specificity and Potency of a Series of Cholecystokinin‐B/Gastrin Receptor Antagonists in vivo

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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 ED50dose of gastrin (0.4 nmoles/kg/hr), was seen at doses of 3, 0.3, 0.1 and 0.1 μmoles/kg/hr, respectively; the corresponding ID50values were 0.4, 0.02, 0.007 and 0.004 μmoles/kg/hr. 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 ID50value 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 antagonistsin vivo, being without measurable agonistic activity. Furthermore, they do not interact with cholecystokinin‐A receptors at the doses tested. Among the cholecystokinin‐B receptor antagonists studied YM022 and RP73870 are superior, the rank order of potency being YM022±RP73870>L‐740,093>L‐365,260.

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