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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
7
|
| pubmed:dateCreated |
1996-8-26
|
| pubmed:abstractText |
We report a systematic probing of the structural requirements of the bradykinin (BK) type 2 (B(2)) receptor for antagonist activity by incorporating N-alkyl-amino acid residues at positions 7 and 8 of a potent antagonist sequence. Compound 1 (D-Arg(0)-Arg(1)-Pro(2)-Hyp(3)-Gly(4)-Thi(5)-Ser(6)-D-Tic(7)-N-Chg (8)-Arg(9), CP-0597)(1,2) is a potent (pA(2) = 9.3, rat uterus; pK(i) = 9.62, binding, human receptor clone) B(2) receptor antagonist devoid of in vitro B(1) antagonist activity (rabbit aorta). Compound 1 exhibits high potency (ED(50) = 29.2 pmol/kg/min, iv, rabbit) and duration of action when tested in models for in vivo B(2) antagonist activity. Although devoid of activity in a classic B(1) isolated tissue assay, B(1) antagonist activity for 1 was demonstrated in vivo, in a LPS-treated, inducible BK(1) receptor rabbit blood pressure model (ED(50) = 1.7 nmol/kg/min). D-Arg(0) of 1 can be formally replaced by an achiral arginine surrogate, without significant loss in antagonist potency on rat uterus (compound 11, B(2) pA(2) = 9.1). Antagonist 13 (Hyp(2), Nchg(8)), pK(i) = 10.2, and agonist 4 (N-methylcyclohexyl-Gly(8)), pK(i) = 10.1, also exhibited substantial binding to guinea pig ileum membrane receptors as well as a human B(2) receptor clone. Very minor structural changes in the N-alkyl amino acid residues in positions 7 and 8 can modify the activity of this class of compounds from being extremely potent antagonists to tight binding partial or full agonists. These studies have resulted in a series of compounds containing inexpensive amino acid residues but which produce broad spectrum BK receptor blocking potency and exceptional in vivo duration of action.
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| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Amino Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Oligopeptides,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Bradykinin B1,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Bradykinin B2,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Bradykinin
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Mar
|
| pubmed:issn |
0022-2623
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
29
|
| pubmed:volume |
39
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
1472-84
|
| pubmed:dateRevised |
2006-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:8691478-Amino Acid Sequence,
pubmed-meshheading:8691478-Amino Acids,
pubmed-meshheading:8691478-Animals,
pubmed-meshheading:8691478-Aorta,
pubmed-meshheading:8691478-Binding, Competitive,
pubmed-meshheading:8691478-Blood Pressure,
pubmed-meshheading:8691478-Female,
pubmed-meshheading:8691478-Guinea Pigs,
pubmed-meshheading:8691478-Humans,
pubmed-meshheading:8691478-Ileum,
pubmed-meshheading:8691478-Magnetic Resonance Spectroscopy,
pubmed-meshheading:8691478-Mass Spectrometry,
pubmed-meshheading:8691478-Molecular Sequence Data,
pubmed-meshheading:8691478-Molecular Structure,
pubmed-meshheading:8691478-Oligopeptides,
pubmed-meshheading:8691478-Protein Binding,
pubmed-meshheading:8691478-Rabbits,
pubmed-meshheading:8691478-Rats,
pubmed-meshheading:8691478-Receptor, Bradykinin B1,
pubmed-meshheading:8691478-Receptor, Bradykinin B2,
pubmed-meshheading:8691478-Receptors, Bradykinin,
pubmed-meshheading:8691478-Structure-Activity Relationship,
pubmed-meshheading:8691478-Uterus
|
| pubmed:year |
1996
|
| pubmed:articleTitle |
Bradykinin receptor antagonists containing N-substituted amino acids: in vitro and in vivo B(2) and B(1) receptor antagonist activity.
|
| pubmed:affiliation |
Department of New Leads Discovery, Cortech, Inc., Denver, Colorado 80221, USA.
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| pubmed:publicationType |
Journal Article
|