SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF DUAL HISTAMINE H-2 AND GASTRIN RECEPTOR ANTAGONISTS WITH NONCYCLIC GASTRIN RECEPTOR ANTAGONISTIC MOIETIES

In order to study structure-activity relationships of dual histamine H -2 and gastrin receptor antagonists as well as to improve their low or al absorbability, their prototype benzodiazepine gastrin receptor anta gonistic moieties were altered to a conformationally flexible noncycli c dipeptide equivalent. This skeletal modification significantly poten tiated the binding affinity of hybrid compounds for the histamine H-2 receptor, whereas their affinity for the gastrin receptor and receptor selectivity over the CCK-A receptor varied widely with the substituen ts on the gastrin moiety. Among them, 1-ylmethylphenoxy)-propylcarbamo yl]propyl}carbamic acid ylcarbamoyl)methyl]carbamoyl}methyl)ureido]-be nzyl ester (7a) showed the highest dual histamine H-2 and gastrin rece ptor antagonistic activities. It also displayed distinct gastric acid antisecretory activity in vivo for two assays, namely, Schild's rat me thod by id administration and the rat pylorus ligation method by oral administration. With the latter case, dose-response relationships were observed for the first time, suggesting its substantially improved or al absorbability. However, 7a did not display distinct in vivo gastric acid antisecretory activity for the assay with Heidenhain pouch dogs. (C) 1997 Elsevier Science Ltd.