Tachyphylactic properties of angiotensin II analogs with bulky and hydrophobic substituents at the N-terminus

Tachyphylactic properties of angiotensin II analogs with bulky and hydrophobic substituents at the N-terminus

Author Motta, S. C. Google Scholar
Poletti, E. F. Google Scholar
Souza, SEG Google Scholar
Corrêa, Silvana Aparecida Alves Autor UNIFESP Google Scholar
Jubilut, G. N. Google Scholar
Paiva, ACM Google Scholar
Shimuta, S. I. Google Scholar
Nakaie, C. R. Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Abstract Tachyphylaxis, defined as the acute loss of response of some smooth muscles upon repeated stimulations with angiotensin II (Ang II), has been shown to be dependent mainly on the N-terminal region of the ligand. To further study the structural requirements for the induction of tachyphylaxis we have synthesized Ang II analogs containing the bulky and very lipophilic substituents 9-fluorenylmethyloxycarbonyl (Fmoc) and 9-fluorenylmethyl ester (OFm) at the alpha-amino (N-alpha-Fmoc-Ang II) or the beta-carboxyl ([Asp(OFm)(1)]-Ang II) groups of the Asp(1) residue, respectively. in binding assays with Chinese hamster ovary cells transfected with the AT(1) Ang II receptor, N-alpha-Fmoc-Ang II bound with high affinity, whereas [Asp(OFm)(1)]-Ang II showed lower affinity. in biological assays, these two analogs were full agonists and showed 30 and 3%, respectively, of the Ang II potency in contracting the guinea-pig ileum smooth muscle. the two analogs induced tachyphylaxis, in spite of the lack of a free amino group in N-alpha-Fmoc-Ang II. Thus, analogs with Fmoc- or OFm-type groups coupled to the Asp(1) residue, whether at the amino or carboxyl functions, induce tachyphylaxis through an unreported mechanism. Based in these findings and those available from the literature, an alternate molecular interaction mode between Ang II N-terminal portion and the AT(1) receptor is proposed to explain the tachyphylactic phenomenon.
Keywords analogs
angiotensin II
AT(1) receptor
tachyphylaxis
Language English
Date 2003-11-01
Published in Journal of Peptide Research. Copenhagen: Blackwell Munksgaard, v. 62, n. 5, p. 227-232, 2003.
ISSN 1397-002X (Sherpa/Romeo, impact factor)
Publisher Blackwell Munksgaard
Extent 227-232
Origin http://dx.doi.org/10.1034/j.1399-3011.2003.00091.x
Access rights Closed access
Type Article
Web of Science ID WOS:000186178700005
URI http://repositorio.unifesp.br/handle/11600/27474

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