YF476 is a new potent and selective gastrin/cholecystokinin‐B receptor antagonist in vitro and in vivo

Background : We newly synthesized YF476 ((R)‐1‐[2,3‐dihydro‐2‐oxo‐1‐pivaloylmethyl‐5‐(2′‐pyridyl)‐1H‐1,4‐benzodiazepin‐3‐yl]‐3‐(3‐methylamino‐phenyl)urea) as a gastrin/cholecystokinin‐B (CCK‐B) receptor antagonist. We investigated the pharmacological profile of YF476 in vitro and in vivo . Methods : We examined the binding properties of YF476 to the rat brain, cloned canine and cloned human gastrin/CCK‐B receptors, and the effect of YF476 on secretagogue‐induced gastric acid secretion in rats and Heidenhain pouch dogs. Results : YF476 replaced the specific binding of [ 125 I]CCK‐8 to the rat brain, cloned canine and cloned human gastrin/CCK‐B receptors, with K i values of 0.068, 0.62 and 0.19 n M , respectively. The affinity of YF476 for rat brain gastrin/CCK‐B receptor was 4100‐fold higher than that for rat pancreatic CCK‐A receptor. In anaesthetized rats, intravenous YF476 inhibited pentagastrin‐induced acid secretion with an ED 50 value of 0.0086 μmol/kg, but did not affect histamine‐ and bethanechol‐induced acid secretion at a dose of 10 μmol/kg. In Heidenhain pouch dogs, intravenous and oral YF476 inhibited pentagastrin‐stimulated gastric acid secretion in a dose‐dependent manner with ED 50 values of 0.018 and 0.020 μmol/kg, respectively, but did not affect histamine‐induced acid secretion. Conclusion : These results suggest that YF476 is an extremely potent and highly selective gastrin/CCK‐B receptor antagonist, and that the gastrin/CCK‐B receptor is not involved in histamine‐ or bethanechol‐induced gastric acid secretion in dogs or rats.