STRUCTURE-ACTIVITY STUDIES OF B-1 RECEPTOR-RELATED PEPTIDES - ANTAGONISTS

We tested several peptides related to des-Arg(9)-bradykinin as stimula nts or inhibitors of B-1 (rabbit aorta, human umbilical vein) and B-2 (rabbit jugular vein, guinea pig ileum, human umbilical vein) receptor s. We also incubated the compounds with purified angiotensin-convertin g enzyme from rabbit lung to test their resistance to degradation. We evaluated apparent affinities (in terms of the affinity constant pA(2) ) of compounds and their potential residual agonistic activities (alph a(E)). Bradykinin and des-Arg(9)-bradykinin were used as agonists for the B-2 and B-1 receptors, respectively. Degradation of peptides by th e angiotensin-converting enzyme was prevented in the presence of a D-r esidue in position 7 of des-Arg(9)-bradykinin. Replacement of Pro(7) w ith D-Tic combined with Leu, Ile, Ala, or D-Tic in position 8 led to w eak B-1 receptor antagonists, some of which had strong residual agonis tic activities on the B-2 receptor preparations. The use of D-beta Nal in position 7, combined with Ile in position 8 and AcLys at the N-ter minal (eg, AcLys[D-beta Nal(7),Ile(8)]des-Arg(9)-bradykinin) gave the most active B-1 receptor antagonist (pA(2) of 8.5 on rabbit aorta and human umbilical vein), which is also partially resistant to enzymatic degradation. Extension of the N-terminal end by Sar-Tyr-epsilon Ahx (u sed for labeling purposes) and even cold-labeling of Tyr with iodine w ere compatible with high, selective, and specific antagonism of the B- 1 receptors. We compared some compounds with some already known B-1 re ceptor antagonists to underline the novelty of new peptidic compounds.