Synthesis and structure-activity relationships of dual histamine H2 and gastrin receptor antagonists with modified benzodiazepine skeletons

Abstract Three different types of dual histamine H 2 and gastrin receptor antagonists, e.g. those bearing a benzazepine, benzoxazepine, or benzothiazepine skeleton instead of the benzodiazepine one as a gastrin receptor antagonistic moiety were synthesized to reduce high hydrophobicity of parent compounds and evaluated for the dual activities. These skeletal modifications significantly potentiated the binding affinity of dual antagonists with histamine H 2 receptor but markedly diminished their binding affinity with the gastrin receptor and the gastrin versus CCK-A receptor selectivity. We evaluated in vivo gastric acid antisecretory activities for some representative compounds by the rat pylorus ligation method for 10 mg kg −1 dose by oral route. However, they exerted only low inhibitory activities for oral dose with % inhibition values ranging between 32 and 53%.