Structure-activity relationships of endothelin-1 analogues

The importance of residues 9 and 10 for endothelin-1 (ET-1) biologic activity was assessed by studying the responses of the guinea pig ileum to [Ala9]-ET-1 and [Ala10]-ET-1. Both analogues induced relaxation followed by contraction. [Ala9]-ET-1 showed similar ED50 value and maximal response to those of ET-1, whereas [Ala10]-ET-1 had a larger ED50 value and was a partial agonist, as was IRL1620. ET-1 and [Ala10]-ET-1 induced similar degrees of tachyphylaxis, whereas [Ala9]-ET-1 induced very little tachyphylaxis, indicating that Lys9 is important for inducing tachyphylaxis. BQ-123, an ETA antagonist, did not inhibit the relaxation. It did inhibit [Ala9]-ET-1- and ET-1-induced contractions but not [Ala10]-ET-1- and IRL1620-induced contractions. Cross-tachyphylaxis and additivity studies indicated that [Ala9]-ET-1, like ET-1, acts at the ETA receptor, whereas [Ala10]-ET-1 behaved as an ETB receptor agonist, like sarafotoxin S6c. Therefore, the residue at position 10 plays a significant role in receptor activation and is a candidate for further exploration of receptor antagonism. FCE27037 (cyclo [D-Cys11-Cys15]-ET-1[8-21]) inhibited the contractile but not the relaxant component of the response induced by IRL1620. These results indicate that FCE27037 is a new ETB antagonist and a useful tool that can discriminate pharmacologically the functionally distinct ETB receptors present in the guinea pig ileum.