In vitro and in vivo activities of reduced-size antagonists of luteinizing hormone-releasing hormone

J Med Chem. 1994 Mar 4;37(5):701-5. doi: 10.1021/jm00031a021.

Abstract

A novel series of octapeptide LHRH antagonists was designed on the basis of the structure of the (2-9) fragment of a LHRH agonist. By adopting a systematic SAR study, we were able to improve first the in vitro activity and then the in vivo LH suppression, raising them up to the range of the decapeptide antagonists NalGlu (51) and A-75998 (50), resulting in A-76154 (49). The octapeptide antagonist A-76154 is the most potent reduced-size LHRH antagonist reported. It suppresses LH in the castrated rat by over 80% for a period of 4 h following sc bolus administration of 30 micrograms/kg.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Castration
  • Drug Design
  • Gonadotropin-Releasing Hormone / analogs & derivatives*
  • Gonadotropin-Releasing Hormone / antagonists & inhibitors*
  • Gonadotropin-Releasing Hormone / chemical synthesis
  • Gonadotropin-Releasing Hormone / chemistry
  • Gonadotropin-Releasing Hormone / pharmacokinetics
  • Gonadotropin-Releasing Hormone / pharmacology
  • Histamine Release / drug effects
  • Luteinizing Hormone / metabolism
  • Mast Cells / drug effects
  • Mast Cells / physiology
  • Molecular Sequence Data
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / pharmacokinetics
  • Oligopeptides / pharmacology
  • Peptide Fragments / chemical synthesis*
  • Peptide Fragments / pharmacokinetics
  • Peptide Fragments / pharmacology
  • Pituitary Gland / drug effects
  • Pituitary Gland / metabolism
  • Rats
  • Structure-Activity Relationship

Substances

  • Oligopeptides
  • Peptide Fragments
  • A 76154
  • Gonadotropin-Releasing Hormone
  • Luteinizing Hormone