SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF DUAL HISTAMINE H-2 AND GASTRIN RECEPTOR ANTAGONISTS WITH MODIFIED BENZODIAZEPINE SKELETONS

Three different types of dual histamine H-2 and gastrin receptor antag onists, e.g. those bearing a benzazepine, benzoxazepine, or benzothiaz epine 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 skeleta l modifications significantly potentiated the binding affinity of dual antagonists with histamine H-2, receptor but markedly diminished thei r binding affinity with the gastrin receptor and the gastrin versus CC K-A receptor selectivity. We evaluated in vivo gastric acid antisecret ory activities for some representative compounds by the rat pylorus li gation method for 10 mg kg(-1) dose by oral route. However, they exert ed only low inhibitory activities for oral dose with % inhibition valu es ranging between 32 and 53%. (C) 1997 Elsevier Science Ltd.