Structure-activity studies of B-1 receptor-related peptides - Antagonists

We tested several peptides related to des-Arg(9)-bradykinin as stimulants or inhibitors of B-1 (rabbit aorta, human umbilical vein) and B-2 (rabbit jugular vein, guinea pig ileum, human umbilical vein) receptors. We also incubated the compounds with purified angiotensin-converting 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 (alpha(E)). Bradykinin and des-Arg(9)-bradykinin were used as agonists for the B-2 and B-1 receptors, respectively. Degradation of peptides by the angiotensin-converting enzyme was prevented in the presence of a D-residue in position 7 of des-Arg(9)-bradykinin. Replacement of Pro(7) with D-Tic combined with Leu, Ile, Ala, or D-Tic in position 8 led to weak B-1 receptor antagonists, some of which had strong residual agonistic 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-terminal (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 (used for labeling purposes) and even cold-labeling of Tyr with iodine were compatible with high, selective, and specific antagonism of the B-1 receptors. We compared some compounds with some already known B-1 receptor antagonists to underline the novelty of new peptidic compounds.