Cyclic hexapeptide endothelin receptor antagonists highly potent for both receptor subtypes ETA and ETB.
A cyclic hexapeptide, cyclo(-D-Asp-Trp-Asp-D-Leu-Leu-D-Trp-), designed from cyclo(-D-Glu-Ala-D-alloisoleucyl-Leu-D-Trp-), an ETA receptor-selective antagonist, possessed not only affinity similar to that of BQ-123 for ETA but also higher affinity for ETB than BQ-123. Further modification led to the discovery of cyclo(-D-Asp-Asp(Php)-Asp-D-Thg-Leu-D-Trp-) (Asp(Php): 1-beta-aspartyl-4-phenylpiperazine; Thg: 2-(2-thienyl)glycine) that inhibited [125I]ET-1 binding to the ETA and ETB receptors with IC50 values of 0.082 nM and 120 nM, respectively. Although this compound possesses 1470-fold less affinity for ETB than for ETA, it behaves as a non-selective antagonist that equipotently inhibits vasoconstriction mediated by both receptor subtypes ETA and ETB.
Kikuchi
T
T
Discovery Research Division, Takeda Chemical Industries, Ltd., Ibaraki, Japan.
Ohtaki
T
T
Kawata
A
A
Imada
T
T
Asami
T
T
Masuda
Y
Y
Sugo
T
T
Kusumoto
K
K
Kubo
K
K
Watanabe
T
T
D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009126:Muscle Relaxation / Q000187:drug effects; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D017466:Receptors, Endothelin / Q000187:drug effects*; D013552:Swine
D010456:Peptides, Cyclic; D017466:Receptors, Endothelin