Conformational analysis of cyclic angiotensin II analogues

Abstract

Conformationally restricted cyclic analogues of angiotensin II (ANG II), Aspl-Arg2-ValLTyr4-ValS-His6-Pro 7-Phe 8, with a link between positions 3 and 5 have considerable biological activity. It is proposed that the spatial arrangement of the pharmacophore groups of Tyr a, His 6 and Phe 8 side chains and the C-terminal carboxyl group in ANG II and active analogues is similar. Conformational analysis of ANG II and two cyclic analogues c[Sar ~, Lys3,GIuS]ANG II and c[Sarl,Hcy3,Mp:]ANG II was performed, and a geometrical comparison of the low-energy conformations of these compounds allowed one to propose a model of receptor-bound conformation in terms of the spatial arrangement of the pharmacophore groups. This model is characterised by the close spatial location of the His6-Phe 8 side chains and the Tyr 4 C-terminal carboxyl group and is stabilised by the electrostatic interaction of Arg z and the C-terminal carboxyl group.

Bicyclic Tripeptide Mimetics with Reverse Turn Inducing Properties

“…The pharmacological evaluation showed that analogues 11 − 14 lacked affinity to the AT 1 receptor and apparently the angiotensin II analogues cannot adopt a conformation that enables binding to the AT 1 receptor. − According to the theoretical conformational analysis, the model compounds 17 and 18 adopt β-turn geometries that could not be classified into the well-defined turn types. Most of the β-turn mimetics available today mimic one of the classical β-turns.…”

New Selective AT2Receptor Ligands Encompassing a γ-Turn Mimetic Replacing the Amino Acid Residues 4−5 of Angiotensin II Act as Agonists

“…35,36 Several models of the bioactive conformation of Ang II when interacting with the AT 1 receptor have been proposed. 32,[37][38][39][40][41][42][43][44] Thus, it has been suggested by several groups that Ang II adopts a turn conformation around the Tyr 4 residue 25,26,29,30,[37][38][39][45][46][47] but also extended conformations of Ang II have been considered. 48 Much less is reported on the structural requirements for AT 2 receptor affinity, [49][50][51][52][53][54][55][56] although it is known that monoand bicyclizations in the 3-5 region of Ang II may give analogues with retained affinity.…”

“…In this context, constrained analogues are important research tools and various cyclization strategies have been employed to introduce conformational constrains in Ang II. − An important driving force for the research is to enable the conversion of peptides into more druglike compounds. Cyclization can be a powerful tool and transform peptide leads into peptidomimetic compounds. , Several models of the bioactive conformation of Ang II when interacting with the AT 1 receptor have been proposed. ,− Thus, it has been suggested by several groups that Ang II adopts a turn conformation around the Tyr 4 residue ,,,,− ,− but also extended conformations of Ang II have been considered . Much less is reported on the structural requirements for AT 2 receptor affinity, − although it is known that mono- and bicyclizations in the 3−5 region of Ang II may give analogues with retained affinity. ,, …”

AT2-Selective Angiotensin II Analogues Containing Tyrosine-Functionalized 5,5-Bicyclic Thiazabicycloalkane Dipeptide Mimetics

“…Although several different models of Ang II binding to the AT 1 receptor have been proposed, − it seems likely that the peptide adopts a reverse turn at the central Tyr 4 residue. − ,− Understanding of the requirements for molecular recognition at the AT 2 receptor is more limited. ,,− The introduction of monocyclic or bicyclic amino acid sequences into the 3−5 region of Ang II has been reported to result in analogues with retained AT 2 affinity, and it was postulated that Ang II binding at the AT 2 receptor might also involve a reverse turn in the Tyr 4 region of the molecule. , Recently an Ang II analogue with high AT 2 affinity and encompassing a γ-turn-like mimetic replacing amino acid residues 4−5 was also reported …”