title: Tachyphylactic properties of angiotensin II analogs with bulky and hydrophobic substituents at the N-terminus.
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 (Nalpha-Fmoc-Ang II) or the beta-carboxyl ([Asp(OFm)1]-Ang II) groups of the Asp1 residue, respectively. In binding assays with Chinese hamster ovary cells transfected with the AT1 Ang II receptor, Nalpha-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 Nalpha-Fmoc-Ang II. Thus, analogs with Fmoc- or OFm-type groups coupled to the Asp1 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 AT1 receptor is proposed to explain the tachyphylactic phenomenon.
authors.affiliation: Departamento de Biofisica da, Universidade Federal de São Paulo-Escola Paulista de Medicina, São Paulo, SP, Brazil.
authors.forename: S C
authors.initials: SC
authors.lastname: Motta
authors.forename: E F
authors.initials: EF
authors.lastname: Poletti
authors.forename: S E G
authors.initials: SE
authors.lastname: Souza
authors.forename: S A A
authors.initials: SA
authors.lastname: Correa
authors.forename: G N
authors.initials: GN
authors.lastname: Jubilut
authors.forename: A C M
authors.initials: AC
authors.lastname: Paiva
authors.forename: S I
authors.initials: SI
authors.lastname: Shimuta
authors.forename: C R
authors.initials: CR
authors.lastname: Nakaie
mesh_terms: D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D057927:Hydrophobic and Hydrophilic Interactions; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011869:Radioligand Assay; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013618:Tachyphylaxis / Q000502:physiology*
chemical_list: C486901:(Asp(OFm)1)-Ang II; C486900:Nalpha-Fmoc-Ang II; D009842:Oligopeptides; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II