Conformational analysis of cyclic angiotensin II analogues

Conformationally restricted cyclic analogues of angiotensin II (ANG II), Asp(1)-Arg(2)-Val(3)-Tyr(4)-Val(5)-His(6)-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(4), 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(1), Lys(3),Glu(5)]ANG II and c[Sar(1),Hcy(3),Mpt(5)]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 His(6)-Phe(5) side chains and the Tyr(4) C-terminal carboxyl group and is stabilised by the electrostatic interaction of Arg(2) and the C-terminal carboxyl group.