Biological activities of photoaffinity labeling analogs of kinins and their irreversible effects on kinin receptors

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Abstract
The peptides of the kinin family, such as kallidin and bradykinin have received much attention because of their implication in such pathophysiological conditions, as inflammation, hypertension, and pain. Many attempts have been made to find specific competitive antagonists for the kinins to characterize the receptors and for human medical applications. Several analogs of bradykinin and [des-Arg9]bradykinin with potentially reactive groups were tested for their biological activities. In these analogs, phenylalanine [Phe] was replaced by the aromatic amino acid (4''-nitro)Phe, (4''-amino)Phe, (4''-azido)Phe and (4''-diazonium)Phe, as well as with other residues. [Des-Arg9]bradykinin and the octapeptide analogs were tested on rabbit aorta strips, an assay organ containing the B1 receptor which is activated by the octapeptide [des-Arg9]bradykinin. Strips of rabbit jugular vein served as bioassays for bradykinin and the nonapeptide analogs, because the rabbit jugular vein bears the receptor B2 which is sensitive to bradykinin nonapeptides. The biological findings support the interpretation that kinins act on 2 different receptor types, since the potency orders of the analog in the 2 bioassays are different. All potential photolabels retained reasonable affinities in the dark, except [(4''-azido)Phe8,des-Arg9]bradykinin, which proved to be a weak and competitive antagonist of [des-Arg9]bradykinin on the rabbit aorta. Inactivation experiments with the unstable (4''-diazonium)Phe-containing peptides did not show any irreversible effect in the 2 bioassays. Photoaffinity labeling experiments with the azido and the nitro peptides gave irreversible and specific effects on both the rabbit aorta and the jugular vein. [(4''-Azido)Phe8,des-Arg9]bradykinin photolyzed at 365 nm on the rabbit aorta reduced the sensitivity of this tissue against [des-Arg9]bradykinin specifically to .apprx. 1/3 of its initial value. [(4''-Azido)Phe5]bradykinin reduced the sensitivity of the rabbit jugular vein to bradykinin by > 50%. The observed irreversible effects were always loss of myotropic activity and never permanent contraction.

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