STRUCTURE-ACTIVITY-RELATIONSHIPS OF ENDOTHELIN-1 ANALOGS

STRUCTURE-ACTIVITY-RELATIONSHIPS OF ENDOTHELIN-1 ANALOGS

Author Miasiro, N. Autor UNIFESP Google Scholar
Decastiglione, R. Google Scholar
Paiva, Antonio Cechelli de Mattos Autor UNIFESP Google Scholar
Institution PHARM FARMITALIA CARLO ERBA
Universidade Federal de São Paulo (UNIFESP)
Abstract 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.
Keywords ENDOTHELIN
ALANINE ANALOGS
RECEPTOR SUBTYPES
GUINEA PIG ILEUM
TACHYPHYLAXIS
ANTAGONISTS
Language English
Date 1995-01-01
Published in Journal Of Cardiovascular Pharmacology. Philadelphia: Lippincott-raven Publ, v. 26, p. S320-S321, 1995.
ISSN 0160-2446 (Sherpa/Romeo, impact factor)
Publisher Lippincott-raven Publ
Extent S320-S321
Origin http://journals.lww.com/cardiovascularpharm/Abstract/1995/06263/Structure_Activity_Relationships_of_Endothelin_1.96.aspx
Access rights Open access Open Access
Type Article
Web of Science ID WOS:A1995TH91200096
URI http://repositorio.unifesp.br/11600/44222

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