Development of a Potent Thrombin Receptor Ligand

The N-terminal thrombin receptor peptide H-Ser-Phe-Leu-Leu-Arg-Asn-Pro-Asn-Asp-Lys-Tyr-Glu-Pro-Phe-OH (1) fully activates the thrombin receptor with an EC50 of 10 microM. Structural features in the tetradecapeptide which are responsible for receptor activation have been elucidated. Agonist potency h...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1995-09, Vol.38 (20), p.4125-4130
Main Authors: Feng, Dong-Mei, Veber, Daniel F, Connolly, Thomas M, Condra, Cindra, Tang, Mei-Jy, Nutt, Ruth F
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Humans
Ligands
Medical sciences
Molecular Sequence Data
Oligopeptides - pharmacology
Pharmacology. Drug treatments
Receptors, Thrombin - agonists
Structure-Activity Relationship
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Summary:The N-terminal thrombin receptor peptide H-Ser-Phe-Leu-Leu-Arg-Asn-Pro-Asn-Asp-Lys-Tyr-Glu-Pro-Phe-OH (1) fully activates the thrombin receptor with an EC50 of 10 microM. Structural features in the tetradecapeptide which are responsible for receptor activation have been elucidated. Agonist potency has been enhanced 1000-fold with the design of the shortened peptide H-Ala-Phe(p-F)-Arg-Cha-HArg-Tyr-NH2 (56). This analog exhibits an EC50 of 0.01 microM and is the most potent agonist for receptor activation reported to date. The monoiodinated derivative H-Ala-Phe(p-F)-Arg-Cha-HArg-Tyr(3-I)-NH2 (59) exhibits an EC50 of 0.03 microM, a level sufficient for development of a radioligand.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00020a029