New Effective Gonadotropin Releasing Hormone Antagonists with Minimal Potency for Histamine Release in Vitro

Article abstract of DOI:10.1021/jm00160a008

In order to minimize the adverse effect of histamine release in the rat of some gonadotropin releasing hormone (GnRH) antagonists, such as 1,D4FPhe²,DTrp³,DArg⁶>-GnRH, new structures with modifications at positions 1, 2, 3, 5, 6, 7, and 10 were synthesized and tested in several biological systems.In vitro: the affinity for the pituitary GnRH receptor was measured as was the ability of the analogues to inhibit GnRH-stimulated release of luteinizing hormone (LH) by dispersed anterior pituitary cells in culture and to release histamine from rat mast cells.In vivo: inhibition of ovulation in the cycling rat was determined after subcutaneous (sc) injection of the peptides at noon on the day of proestrus; the duration of action of the peptides was evaluated by measuring LH levels in the castrated male rat after sc injection of some selected analogues. 1,D4ClPhe²,D3Pal³,Arg⁵,D-4-p-methoxybenzoyl-2-aminobutyric acid⁶,DAla¹⁰>-GnRH was found to be one of the most potent analogues of this series, causing a 100percent inhibition of ovulation at 5 μg/kg or less.Release of histamine was observed at doses 10-25 times required for 1,D4Phe²,DTrp³,DArg⁶>-GnRH.Thus, introduction of arginine in position 5 with a hydrophobic amino acid in position 6 is compatible with high potency in several biological systems and results in compounds with lowered potency to release histamine compared to homologous peptides with tyrosine in position 5 and D-arginine in position 6.