title: Novel gonadotropin-releasing hormone antagonists: peptides incorporating modified N omega-cyanoguanidino moieties.
abstract: 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.
authors.affiliation: Salk Institute for Biological Studies, La Jolla, California 92186-5800.
authors.forename: P
authors.initials: P
authors.lastname: Theobald
authors.forename: J
authors.initials: J
authors.lastname: Porter
authors.forename: C
authors.initials: C
authors.lastname: Rivier
authors.forename: A
authors.initials: A
authors.lastname: Corrigan
authors.forename: W
authors.initials: W
authors.lastname: Hook
authors.forename: R
authors.initials: R
authors.lastname: Siraganian
authors.forename: M
authors.initials: M
authors.lastname: Perrin
authors.forename: W
authors.initials: W
authors.lastname: Vale
authors.forename: J
authors.initials: J
authors.lastname: Rivier
mesh_terms: D000818:Animals; D001681:Biological Assay; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000494:pharmacology; D006146:Guanidines / Q000737:chemistry*; D006636:Histamine Release / Q000187:drug effects; D007986:Luteinizing Hormone / Q000378:metabolism; D009570:Nitriles / Q000737:chemistry*; D010060:Ovulation / Q000187:drug effects; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D006146:Guanidines; D009570:Nitriles; D010455:Peptides; C070464:azaline; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone