Orally active nonpeptide bradykinin (BK) B2 receptor antagonists have been discovered by using directed random screening and chemical modification. These compounds displaced [3H]BK binding to B2 receptors in guinea-pig ileum membranes, rat uterus membranes and human lung fibroblasts with nanomolar IC50s. They did not inhibit different specific radio-ligand bindings to other receptor sites including B2 receptors. In isolated guinea-pig ileum preparations, these compounds had no agonistic effect on smooth muscle contraction at 10(-6) M, and caused parallel rightward shifts of the concentration-response curves to BK on contraction with higher p A2 values. They also blocked human B2 receptor-mediated phosphatidylinositol hydrolysis without agonistic effect. In vivo, the oral administrations of these antagonists potently inhibited BK-induced bronchoconstriction in guinea-pigs. They also reduced carrageenin-induced paw edema and caerulein-induced pancreatitis in rats. Moreover, these compounds alleviated kaolin-induced pain in mice by oral administration. These results show that our compounds are potent, selective, and orally active BK B2 receptor antagonists and that they may have therapeutic potential against inflammatory diseases and pain.