Inhibitory activity of analogues of luteinizing hormone-releasing hormone (LH-RH) in vitro and in vivo.

Improved inhibitors of LH-RH are those which, beside removal of the histidine residue at position 2 of LH-RH, include replacement of glycine at position 6 by a D-amino acid. A still better modification is replacement of the histidine residue at position 2 by D-phenylalanine. As examples, when tested in pituitary cells in culture, [Des-His2]LH-RH, [Des-His2, D-Leu6]LH-RH, [Des-His2, D-Phe6]-LH-RH, [D-Phe2]LH-RH, [D-Phe2, D-Leu6]LH-RH and [D-Phe2, D-Phe6]LH-RH inhibit 50% of LH release induced by LH-RH at molar ratios (MR50S) of 3000, 500, 60, 1000, 150 and 25, respectively. [D-Phe2, D-Phe6, D-Phe7]LH-RH, [D-Phe2, Phe3, D-Phe6]LH-RH and [D-Phe2, Phe5, D-Phe6]LH-RH have MR50 values of respectively 400, 100, and 75. When evaluated in vivo, some of the mentioned structural modifications permit inhibition of LH-RH action at molar ratios lower than observed in vitro. At a 500 molar ratio, [D-Phe2, Phe5, D-Phe6]-LH-RH inhibits the plasma LH rise induced by LH-RH by 75% up to 5 h after its injection. When administered at 12.00 hours at the dose of 2 mg, this analogue inhibits the spontaneous pro-oestrus LH surge and ovulation by 85 and 75%, respectively.