NOVEL GONADOTROPIN-RELEASING-HORMONE ANTAGONISTS - PEPTIDES INCORPORATING MODIFIED N-OMEGA-CYANOGUANIDINO MOIETIES

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-mu-g/rat with an ED50 in the in vitro histamine release assay comparable to that of GnRH itself.