CYCLIC HEXAPEPTIDE ENDOTHELIN RECEPTOR ANTAGONISTS HIGHLY POTENT FOR BOTH RECEPTOR SUBTYPES ET(A) AND ET(B)

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 ET(A) but also higher affinity for ET(B) than BQ-123. Further modification led to the discovery of cycle(-D-Asp-Asp (Php)-Asp-D-Thg-Leu-D-Trp-) (Asp(Php): 1-beta-aspartyl-4-phenylpiperazine; Thg: 2-(2-thienyl)glycine) that inhibited [I-125]ET-1 binding to the ET(A) and ET(B) receptors with IC50 values of 0.082 nM and 120 nM, respectively. Although this compound possesses 1470-fold less affinity for ET(B) than for ET(A), it behaves as a non-selective antagonist that equipotently inhibits vasoconstriction mediated by both receptor subtypes ET(A) and ET(B). (C) 1994 Academic Press, Inc.