Gonadotropin-releasing hormone antagonists with N omega-triazolylornithine, -lysine, or -p-aminophenylalanine residues at positions 5 and 6.

摘要: In order to be used as fertility regulators in humans, gonadotropin releasing hormone (GnRH) antagonists must extremely potent and long acting exhibit negligible side effects such stimulating histamine release. To this aim, we have recently synthesized a series of analogues with the standard Ac-DNal1-DCpa2-DPal3 substitutions, where N omega-amino function ornithine, lysine, or p-aminophenylalanine (Aph) was converted aminotriazolyl (atz) derivatives at positions 5 6 further modifications 7 10. The were tested for their ability bind pituitary cell membranes, release mast assay, inhibit luteinizing (LH) secretion by castrated male rats cultured cells, interfere ovulation intact female rats. While subcutaneous (sc) injection 50 micrograms Azaline A (7, [Ac-DNal1,DCpa2,DPal3,Lys5(atz),DLys6++ +(atz),ILys8,DAla10]GnRH) dissolved 0.2 mL an aqueous media significantly inhibited LH rat 24 h, same dose B (11), [Ac-DNal1,DCpa2,DPal3,Aph5(atz),DAph6++ +(atz),ILys8,DAla10]GnRH, 72 h. similar duration action observed Antide ([Ac-DNal1,DCpa2,DPal3,Lys5(Nic),DLys6(Nic ),ILys8,DAla10]GnRH) but not Nal-Glu ([Ac-DNal1,DCpa2,DPal3,Arg5,4-(pmethoxybenzoy l)-D-2-Abu6,DAla10]GnRH). paradigm, 5-fold dilution peptide (50 1 mL) use three sites rather than one resulted shorter most peptides tested. This suggested that might result slow from site(s). investigate possibility, injected intravenously (i.v.) doses (10, 50, 250 micrograms) At all doses, both lowered levels 8 By (250 still measurably secretion. Finally, only active 48 These findings demonstrate subtle structural will yield different half-lives after iv administration. led us other on action. We systematic substitutions (NMeLeu) 10 (Pro9-NHEt, Gly-NH2) found deleterious. Of interest observation DAla10-NH2 substitution enzymatic stability under conditions tested.(ABSTRACT TRUNCATED AT 400 WORDS)