A novel generation of peptidic bradykinin B_1 receptor antagonist bearing lipidic moiety

摘要

Bradykinin(BK),an autacoid nonapeptide,plays an important role in normal physiological processes in healthy individuals,as well as in acute and chronic pathological conditions.BK can bind to two known G-protein-coupled receptors named BKB_1R and BKB_2R.The BKB_2R is constitutively expressed in most cell types,whereas the BKB_1R is induced by various pro-inflammatory stimuli(LPS,cytokines).Recent data indicate that activation of the BKB_1R is important in various models of chronic inflammation or persistent hyperalgesic conditions.A number of potent first generation antagonists of the BKB_1R have been developed.Nonetheless,the need remains to provide peptidic BKB_1R antagonists that present very good to high potency,affinity,selectivity and specificity for the BKB|R,with chemical features that favor their absorption and general distribution(pharmacokinetic)in the body in order to optimize potency and duration of action in vivo,with a minimal toxicological/toxicokinetic profile.In the present study the N-terminal position of R-715-a potent,selective,and specific BKB_1R antagonist -has been modified with lipidic acyl side chains to bring changes to both the physical and pharmacological properties of the antagonists.A variation in the length of the alkyl side chain(6-12 carbon atoms)was done in order to determine the optimal length for antagonist activity.Herein,we describe the preparation of such BKB_1R antagonists and discuss the impact of various chain lengths on the biological activity in various in vitro pharmacological preparations.