119018-01-8Relevant articles and documents
New Effective Gonadotropin Releasing Hormone Antagonists with Minimal Potency for Histamine Release in Vitro
Rivier, Jean E.,Porter, John,Rivier, Catherine L.,Perrin, Marylin,Corrigan, Anne,et al.
, p. 1846 - 1851 (2007/10/02)
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.
