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 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.
Feng
D M
DM
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Veber
D F
DF
Connolly
T M
TM
Condra
C
C
Tang
M J
MJ
Nutt
R F
RF
D000595:Amino Acid Sequence; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D018179:Receptors, Thrombin / Q000819:agonists*; D013329:Structure-Activity Relationship
D008024:Ligands; D009842:Oligopeptides; D018179:Receptors, Thrombin