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.
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism; D008297:Male; D010060:Ovulation / Q000187:drug effects; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D013329:Structure-Activity Relationship; D013997:Time Factors
D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone