Novel gonadotropin-releasing hormone antagonists: peptides incorporating modified N omega-cyanoguanidino moieties

J Med Chem. 1991 Aug;34(8):2395-402. doi: 10.1021/jm00112a013.


In order to minimize the deleterious effects of histamine release resulting from the administration to rats and humans of some potent gonadotropin-releasing hormone (GnRH) antagonists, various arginine residues were replaced with the less basic N omega-cyano-N omega-alkyl- or -arylhomoarginine, -arginine, or -p-aminophenylalanine and N omega-triazolyllysine, -ornithine or -p-aminophenylalanine residues in active analogues. These novel analogues were synthesized on a solid-phase support via a two-step modification of the N omega-NH2 of lysine, ornithine, or p-aminophenylalanine residues in otherwise protected resin bound peptides. Most analogues were tested in the rat antiovulatory assay (AOA) and three in vitro assays; a pituitary cell culture assay, a binding assay to pituitary cell membranes, and a histamine release assay. Introduction of the cyanoguanidino and N omega-triazolyl moieties into GnRH analogues yielded several water-soluble antagonists which showed a desirable therapeutic ratio (low histamine release activity to high in vivo potency). Among them, "Azaline" (10, [Ac-DNal1,DCpa2,DPal3,Lys5(atz), DLys6(atz),ILys8,DAla10]GnRH), inhibited ovulation in the rat by 90% at 2 micrograms/rat with an ED50 in the in vitro histamine release assay comparable to that of GnRH itself.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Biological Assay
  • Cells, Cultured
  • Chemical Phenomena
  • Chemistry
  • Female
  • Gonadotropin-Releasing Hormone / analogs & derivatives
  • Gonadotropin-Releasing Hormone / antagonists & inhibitors*
  • Gonadotropin-Releasing Hormone / chemical synthesis
  • Gonadotropin-Releasing Hormone / pharmacology
  • Guanidines / chemistry*
  • Histamine Release / drug effects
  • Luteinizing Hormone / metabolism
  • Nitriles / chemistry*
  • Ovulation / drug effects
  • Peptides / chemical synthesis
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Pituitary Gland / drug effects
  • Pituitary Gland / metabolism
  • Rats
  • Structure-Activity Relationship


  • Guanidines
  • Nitriles
  • Peptides
  • azaline
  • Gonadotropin-Releasing Hormone
  • Luteinizing Hormone