Structure-Activity Studies of B 1 Receptor–Related Peptides

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Abstract
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 (α 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 -βNal in position 7, combined with Ile in position 8 and AcLys at the N-terminal (eg, AcLys[ d- βNal 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-εAhx (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.

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