BRADYKININ ANTAGONISTS IN HUMAN SYSTEMS - CORRELATION BETWEEN RECEPTOR-BINDING, CALCIUM SIGNALING IN ISOLATED CELLS, AND FUNCTIONAL-ACTIVITY IN ISOLATED ILEUM

The determination of the relationship between ligand affinity and bioa ctivity is important for the understanding of receptor function in bio logical systems and for drug development. Several physiological and pa thophysiological functions of bradykinin (BK) are mediated via the B-2 receptor. In this study, we have examined the relationship between B- 2 receptor (soluble and membrane-bound) binding of BK peptidic antagon ists, inhibition of calcium signalling at a cellular level, and in vit ro inhibition of ileum contraction. Only human systems were employed i n the experiments. Good correlations between the studied activities of BK antagonists were observed for a variety of different peptidic stru ctures. The correlation coefficients (r) were in the range of 0.905 to 0.955. In addition, we analyzed the effect of the C-terminal Arg(9) r emoval from BK and its analogs on B-2 receptor binding. The ratios of binding constants (K-i(+Arg)/K-i(-Arg)) for the Arg(9) containing comp ounds and the corresponding des-Arg(9) analogs varied from about 10 to 250,000. These ratios strongly depend on the chemical structures of t he compounds. The highest ratios were observed for two natural agonist pairs, BK/des-Arg(9)-BK and Lys(0)-BK/des-Arg(9)-Lys(0)-BK. (C) 1997 Elsevier Science Inc.