Structure-activity relationships for the competitive angiotensin antagonist [sarcosine1, O-methyltyrosine4]angiotensin II (sarmesin)

Analogues of the competitive angiotensin antagonist [Sar1,Tyr(Me)4]ANG II (sarmesin) in which the sarcosine-1, O-methyltyrosine-4, and phenylalanine-8 residues were modified have been synthesized by the solid-phase method. The agonist and antagonist potencies of the 23 peptides synthesized were dete...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1986-06, Vol.29 (6), p.1121-1124
Main Authors: Goghari, Mahesh H, Franklin, Kevin J, Moore, Graham J
Format: Article
Language:English
Subjects:
Angiotensin II - analogs & derivatives
Angiotensin II - antagonists & inhibitors
Angiotensin II - chemical synthesis
Angiotensin II - pharmacology
Animals
Biological and medical sciences
Female
General pharmacology
Medical sciences
Pharmacology. Drug treatments
Physicochemical properties. Structure-activity relationships
Rats
Rats, Inbred Strains
Structure-Activity Relationship
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Summary:Analogues of the competitive angiotensin antagonist [Sar1,Tyr(Me)4]ANG II (sarmesin) in which the sarcosine-1, O-methyltyrosine-4, and phenylalanine-8 residues were modified have been synthesized by the solid-phase method. The agonist and antagonist potencies of the 23 peptides synthesized were determined in the rat isolated uterus assay. At position 1, replacement of Sar with Asp, Ala, or Pro gave inactive analogues, and deletion of the N-terminal amino acid produced inactive heptapeptides for all analogues investigated. At position 4, substitution of Tyr with Tyr(Et), D-Tyr, D-Phe, Ile, Thr, or Hyp resulted in inactive analogues, whereas substitution of Phe gave a potent competitive antagonist (pA2 = 7.9), which retained significant agonist activity (22%). For position 8, [Sar1,Tyr(Me)4,Ile8]ANG II and [Sar1,Phe4,Ile8]ANG II were weaker antagonists (pA2 = 6.6 and 6.7, respectively) than [Sar1,Ile8]ANG II (pA2 apparent = 8.1) and, moreover, were reversible competitive antagonists. These findings demonstrate that the structural requirements for receptor blockade by sarmesin are remarkably stringent--modifications at positions 1, 4, and 8 markedly reduce the antagonist activity of this peptide.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00156a035