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- l)-1 H-1,4-benzodiazepin-3-yl]-3-(3-methylamino-phe as a gastrin/cholecysto kinin-B (CCK-B) receptor antagonist. We investigated the pharmacologic al profile of YF476 in vitro and in vivo. Methods: We examined the bin ding properties of YF476 to the rat brain, cloned canine and cloned hu man gastrin/CCK-B receptors, and the effect of YF476 on secretagogue-i nduced gastric acid secretion in rats and Heidenhain pouch dogs. Resul ts: YF476 replaced the specific binding of [I-125]CCK-8 to the rat bra in, cloned canine and cloned human gastrin/CCK-B receptors, with K-i v alues of 0.068, 0.62 and 0.19 nM, respectively. The affinity of YF476 for rat brain gastrin/CCK-B receptor was 4100-fold higher than that fo r rat pancreatic CCK-A receptor. In anaesthetized rats, intravenous YF 476 inhibited pentagastrin-induced acid secretion with an ED(50) value of 0.0086 mu mol/kg, but did not affect histamine- and bethanechol-in duced acid secretion at a dose of 10 mu mol/kg. In Heidenhain pouch do gs, intravenous and oral YF476 inhibited pentagastrin-stimulated gastr ic acid secretion in a dose-dependent manner with ED(50) values of 0.0 18 and 0.020 mu mol/kg, respectively, but did not affect histamine-ind uced acid secretion. Conclusion: These results suggest that YF476 is a n extremely potent and highly selective gastrin/CCK-B receptor antagon ist, and that the gastrin/CCK-B receptor is not involved in histamine- or bethanechol-induced gastric acid secretion in dogs or rats.