METHYLATION IN POSITION-1 AND POSITION-7 OF ANGIOTENSIN-II - A STRUCTURE-ACTIVITY RELATIONSHIP STUDY

Six analogues of angiotensin II (Ang) were synthesized with modificati ons in positions 1 and 7. The study was undertaken in order to learn m ore about the influence of alkylations in positions 1 and 7 and their interdependence. Previous studies have shown that x,x-dimethylation of Gly (aminoisobutyric acid, Aib) in position 1 produces quite potent a nalogues, as does N-methylation of Gly (sarcosine). Combination of bot h C-x- and N-2-methylations to N-Me-Aib(1), however, did not produce a n affinity increase. Decyclisation of the Pro(7)-residue produced mode rately active analogues with position 7 N-methylation and inactive ana logues if the N-alkylation was suppressed. In order to investigate a p ossible stereochemical interdependence of positions 1 and 7, a group o f peptides with combinations of position 1 and 7 alkylations were inve stigated. The following analogues were prepared: [Sar(1),Aib(7)]Ang, [ Sar(1),Aib(7), Leu(8)]Ang, [Aib(1,7)]Ang, [Aib(1,7),Leu(8)]Ang, [N-Me- Aib(1),Aib(7)]Ang, [N-Me-Aib(1),Aib(7),Leu(8)]Ang. They were synthesiz ed by classical solid phase synthesis using the BOC-TFA-HF scheme. The biological properties of these peptides were assessed on the rabbit a orta preparation and their binding potencies were measured on bovine a drenal membranes. Both on agonistic and antagonistic [Leu(8)]Ang analo gues single Aib substitutions in position 1 or 7 induced affinity redu ction in both bioassays. Simultaneous Aib modifications in positions 1 and 7 induced more important affinity loss in a synergic manner in bo th bioassays and as well for agonists and antagonists. The N-Me-Aib(1) modifications induce similar affinity loss with or without concomitan t Aib(7) modification. Agonistic (Phe(8)) analogues containing Aib in position 7 all have reduced intrinsic activity, indicating for the fir st time an influence of this position on the activation mechanism of t he Ang receptor of the Type AT(1). (C) Munksgaard 1993.