A NEW-TYPE OF BRADYKININ B-2 RECEPTOR ANTAGONISTS - BRADYKININ ANALOGS WITH N-ALKYL AMINO-ACIDS AT POSITION 2

It is commonly assumed that bradykinin B-2 receptor antagonists bind t o a receptor site partially different from that for agonists. Thus, it is likely that there exists more than one key modification to convert bradykinin receptor agonists into antagonists. In this respect, [L-NM ePhe(2)]-BK represents the basic structure of a new type of bradykinin B-2 receptor antagonists without any replacement at position 7. This compound inhibits both in vitro bradykinin-induced contraction of the guinea pig lung strip and in vivo bradykinin-induced bronchoconstricti on. Furthermore, this analog shows analgesic activity, blocks in a dos e-dependent manner the bradykinin-induced Ca2+ release from macrophage s and inhibits at a concentration of 10(-13) M the bradykinin-induced cytokine release from mononuclear cells. Combinations with structural modifications previously performed for other B-2 receptor antagonists rather reduce than enhance the potency.