STRUCTURE-ACTIVITY-RELATIONSHIPS OF ENDOTHELIN-1 ANALOGS

• Autor(a) principal: Miasiro, N. [UNIFESP]
• Data de Publicação: 1995
• Outros Autores: Decastiglione, R., Paiva, Antonio Cechelli de Mattos [UNIFESP]
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UNIFESP
• Texto Completo: http://journals.lww.com/cardiovascularpharm/Abstract/1995/06263/Structure_Activity_Relationships_of_Endothelin_1.96.aspx; http://repositorio.unifesp.br/handle/11600/44222
• topic: ENDOTHELIN; ALANINE ANALOGS; RECEPTOR SUBTYPES; GUINEA PIG ILEUM; TACHYPHYLAXIS; ANTAGONISTS

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 [Ala(9)]-ET-1 and [Ala(10)]-ET-1. Both analogues induced relaxation followed by contraction. [Ala(9)]-ET-1 showed similar ED(50) value and maximal response to those of ET-1, whereas [Ala(10)]-ET-1 had a larger ED(50) value and was a partial agonist, as was IRL1620. ET-1 and [Ala(10)]-ET-1 induced similar degrees of tachyphylaxis, whereas [Ala(9)]-ET-1 induced very little tachyphylaxis, indicating that Lys(9) is important for inducing tachyphylaxis. BQ-123, an ET(A) antagonist, did not inhibit the relaxation. It did inhibit [Ala(9)]-ET-1- and ET-1-induced contractions but not [Ala(10)]-ET-1- and IRL1620-induced contractions. Cross-tachyphylaxis and additivity studies indicated that [Ala(9)]-ET-1, like ET-1, acts at the ET(A) receptor, whereas [Ala(10)]-ET-1 behaved as an ET(B) 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 (cycle [D-Cys(11)-Cys(15)]-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 ET(B) antagonist and a useful tool that can discriminate pharmacologically the functionally distinct ET(B) receptors present in the guinea pig ileum.