Structure-activity studies of endothelin leading to novel peptide ETA antagonists.
With the goal of producing receptor antagonists, numerous monocyclic and bicyclic endothelin analogs were prepared and tested for vasoconstrictor activity, receptor affinity and functional antagonist activity. Bis-penicillamine endothelin analogs containing Ala or Asn at position 18 were functional antagonists, with Ki values of 20-40 nM but KB values of about 1 microM (e.g., [Pen1,11, Nle7, Ala18]-endothelin-1, Ki = 42 nM, KB = 1.2 microM). While these peptides are antagonists at the ETA receptor, they appear to be at least partial agonists at another receptor subtype.
Hunt
J T
JT
Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000.
Lee
V G
VG
McMullen
D
D
Liu
E C
EC
Bolgar
M
M
Delaney
C L
CL
Festin
S M
SM
Floyd
D M
DM
Hedberg
A
A
Natarajan
S
S
D000595:Amino Acid Sequence; D000818:Animals; D002339:Carotid Arteries; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000031:analogs & derivatives; D016232:Endothelins / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014661:Vasoconstriction / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C089337:endothelin-1, Pen(1,11)-Nle(7)-Ala(18)-; C089336:endothelin-1, Pen(1,11)-Nle(7)-Asn(18)-