Structure-activity relationship of analogues of endothelin-1: dissociation of hypotensive and pressor actions

Abstract

The structural requirements of endothelin-1 to evoke depressor and pressor responses were studied in conscious rats. Formylation of the C-terminal Trp eliminated the depressor but not the pressor activity of endothelin-1. Oxidation of Met 7 in this analogue restored the hypotensive activity. Destruction of the Cys 1-Cys 15 disulphide bridge led to a weak agonist with both depressor and pressor activities. Formylalion of Trp 21 in this analogue resulted in a complete loss of biological activity. These results indicate that Met 7 and the indole moiety of Trp 21 are important for the expression of the depressor activity of endothelin-1 whereas the intramolecular loop structure is less important. The results also provide further evidence that the depressor and pressor effects of endothelin-1 are mediated through different receptors.