Antagonist, partial agonist and antiproliferative actions of B‐9870 (CU201) as a function of the expression and density of the bradykinin B 1 and B 2 receptors

Background and purpose: A bradykinin (BK) B 2 receptor (B 2 R) antagonist, B‐9870 (CU201), has been proposed to behave as a ‘biased agonist’ at B 2 Rs and to exert anti‐neoplasic effects. It was unclear whether these effects were determined by the activation of B 2 Rs by the drug. B‐9870 was evaluated for antagonism or stimulation of several responses mediated by the rabbit B 2 R or B 1 receptor (B 1 R); its anti‐proliferative activity was also characterized. Experimental approach and key results: B‐9870 was an insurmountable B 2 R antagonist in the rabbit jugular vein contractility assay, but a partial agonist in HEK 293 cells expressing the rabbit B 2 R or a green fluorescent protein (GFP) conjugate of the latter (ERK1/2 phosphorylation, [Ca 2+ ] i , [ 3 H]‐arachidonate release, endocytosis). The agonist‐like effects of B‐9870 were inhibited by the B 2 R antagonist LF 16.0687 and absent in untransfected cells. In addition, B‐9870 was a surmontable antagonist of the rabbit B 1 R in the aorta contractility assay, and blocked Lys‐des‐Arg 9 ‐BK‐induced ERK1/2 phosphorylation in HEK 293 cells expressing a fluorescent B 1 R conjugate. B‐9870 inhibited the growth of MDA‐MB‐231 cells. The latter effect was not influenced by B 1 R or B 2 R antagonists and was not apoptotic. MDA‐MB‐231 cells expressed a small population of B 2 Rs but no B 1 Rs; they responded to BK (small calcium transients) and B‐9870 behaved as an antagonist. Conclusion and implications: B‐9870 is a dual B 1 R and B 2 R antagonist with confirmed stimulating effects at the B 2 R in high expression systems only. Its cell type‐specific anti‐proliferative effect occurs at a high concentration, independently from kinin receptors and apoptosis. British Journal of Pharmacology (2007) 150 , 369–379. doi: 10.1038/sj.bjp.0706982