Structure-activity studies of endothelin leading to novel peptide ETA antagonists

J T Hunt; V G Lee; D McMullen; E C Liu; M Bolgar; C L Delaney; S M Festin; D M Floyd; A Hedberg; S Natarajan

doi:10.1016/s0968-0896(00)82103-3

Structure-activity studies of endothelin leading to novel peptide ETA antagonists

Bioorg Med Chem. 1993 Jul;1(1):59-65. doi: 10.1016/s0968-0896(00)82103-3.

Authors

J T Hunt¹, V G Lee, D McMullen, E C Liu, M Bolgar, C L Delaney, S M Festin, D M Floyd, A Hedberg, S Natarajan, et al.

Affiliation

¹ Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000.

PMID: 8081838
DOI: 10.1016/s0968-0896(00)82103-3

Abstract

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.

MeSH terms

Amino Acid Sequence
Animals
Carotid Arteries
Endothelin Receptor Antagonists*
Endothelin-1 / analogs & derivatives
Endothelins / chemistry
Endothelins / pharmacology*
Guinea Pigs
Molecular Sequence Data
Muscle, Smooth, Vascular / drug effects
Rabbits
Radioligand Assay
Rats
Receptor, Endothelin A
Receptors, Endothelin / metabolism
Structure-Activity Relationship
Vasoconstriction / drug effects

Substances

Endothelin Receptor Antagonists
Endothelin-1
Endothelins
Receptor, Endothelin A
Receptors, Endothelin
endothelin-1, Pen(1,11)-Nle(7)-Ala(18)-
endothelin-1, Pen(1,11)-Nle(7)-Asn(18)-