Methylation in positions 1 and 7 of angiotensin II. A structure-activity relationship study.
Six analogues of angiotensin II (Ang) were synthesized with modifications in positions 1 and 7. The study was undertaken in order to learn more about the influence of alkylations in positions 1 and 7 and their interdependence. Previous studies have shown that alpha, alpha-dimethylation of Gly (aminoisobutyric acid, Aib) in position 1 produces quite potent analogues, as does N-methylation of Gly (sarcosine). Combination of both C alpha- and N alpha-methylations to N-Me-Aib1, however, did not produce an affinity increase. Decyclisation of the Pro7-residue produced moderately active analogues with position 7 N-methylation and inactive analogues if the N-alkylation was suppressed. In order to investigate a possible stereochemical interdependence of positions 1 and 7, a group of peptides with combinations of position 1 and 7 alkylations were investigated. The following analogues were prepared: [Sar1,Aib7]Ang, [Sar1,Aib,Leu8]Ang, [Aib1,7,Leu8]Ang, [Aib1,7,Leu8]Ang, [N-Me-Aib1,Aib7]Ang, [N-Me-Aib1,Aib7,Leu8]Ang. They were synthesized by classical solid phase synthesis using the BOC-TFA-HF scheme. The biological properties of these peptides were assessed on the rabbit aorta preparation and their binding potencies were measured on bovine adrenal membranes. Both on agonistic and antagonistic [Leu8]Ang analogues single Aib substitutions in position 1 or 7 induced affinity reduction in both bioassays. Simultaneous Aib modifications in positions 1 and 7 induced more important affinity loss in a synergic manner in both bioassays and as well for agonists and antagonists. The N-Me-Aib1 modifications induce similar affinity loss with or without concomitant Aib7 modification.(ABSTRACT TRUNCATED AT 250 WORDS)
Cordopatis
P
P
Department of Chemistry, University of Patras, Greece.
Manessi-Zoupa
E
E
Theodoropoulos
D
D
Bossé
R
R
Bouley
R
R
Gagnon
S
S
Escher
E
E
D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D066298:In Vitro Techniques; D008745:Methylation; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011817:Rabbits; D013329:Structure-Activity Relationship
D000804:Angiotensin II