Linked Life Data

2329570

Source:http://linkedlifedata.com/resource/pubmed/id/2329570

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
1990-5-29
pubmed:abstractText
A series of analogues of the recently reported angiotensin II (AII) antagonist [Sar1]AII-(1-7)-amide or des-Phe8[Sar1]AII (3) have been prepared by solid-phase synthesis and purified by reverse-phase liquid chromatography. The agonist and antagonist properties of these carboxy-truncated analogues of AII were determined in the isolated rabbit aorta assay. In the analogues tested, replacement of aspartic acid in position 1 by sarcosine was found necessary to produce significant antagonist activity. At position 7 of the des-Phe8 analogues, prolinamide could be replaced by proline without significant change in the biological activity. However, substitution of 7-prolinamide by either glycinamide or sarcosinamide provided inactive peptides. Methylation of the 4-tyrosine in [Sar1]AII-(1-7)-NH2 preserved the antagonist potency in isolated rabbit aorta. Deletion of the proline at position 7 resulted in inactive hexapeptides, both in the Asp1 and Sar1 series. However synthesis of the N,N-dimethyl amide at the N-terminus afforded hexapeptide [Sar1]AII-(1-6)-N(CH3)2 (10) with a pA2 value of 7.05. All the antagonistic peptides synthesized were fully reversible, competitive antagonists in vitro. These findings indicate that the structural requirements for receptor blockade by these C-truncated analogues are quite stringent with respect to the nature of the amino acid at positions 1 and 6/7. The analogues 2, 3, 7, 10, 11 (saralasin), and 12 (sarmesin) were tested in vivo in the anesthetized rat and were found to inhibit the AII pressor response. In addition, 3 inhibited angiotensin II stimulated aldosterone release from isolated rat adrenal zona glomerulosa cells and had no agonist activity by itself at the doses tested. Interestingly, analogue 3, when injected intracerebroventricularly in conscious rats, failed to antagonize the dipsogenic response to an angiotensin II icv injection and this reflects some heterogeneity in the AII receptor population. Peptide 3 is the first example of an antagonist that discriminates between peripheral and brain receptor subtypes.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:volume
33
pubmed:owner
NLM
pubmed:authorsComplete
N
pubmed:pagination
1477-82
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed:year
1990
pubmed:articleTitle
Structure-activity relationships for the carboxy-terminus truncated analogues of angiotension II, a new class of angiotensin II antagonists.
pubmed:affiliation
Cardiovascular Diseases Research, Monsanto Life Sciences, Research Center, Chesterfield, Missouri 63198.
pubmed:publicationType
Journal Article