Branched-chain analogues of luteinizing hormone-releasing hormone

Benzoyl-, acetylsalicylyl-, indomethacinyl-, pyroglutamylhistidyl-, and pyroglutamyl-D-phenylalanyl-D-tryptophanylseryltyrosyl groups were attached to a moderately active inhibitory analogue of LH-RH, [D-Phe2,D-Trp3-D-Lys6]-LH-RH, via the epsilon-amino group of the lysine residue. The resulting compounds were assayed for anti-LH-RH activity and for their ability to block ovulation in the rat. The decrease in polarity and increase in size of the lysine side chain resulting from addition of the aromatic acyl groups gave almost no increase in inhibitory activity. Addition of the dipeptide, less than Glu-His, also had little effect on potency. However, incorporation of the pentapeptide sequence to give a branched pentadecapeptide with essentially two N termini resulted in antiovulatory activity greater than the parent peptide or any other analogue thus far tested by us. The corresponding agonist peptide, [Nepsilon-(less than Glu-His-Trp-Ser-Tyr)-D-Lys6]-LH-RH, was also synthesized and tested for LH- and FSH-releasing activity. Surprisingly, it was no more active than [D-Lys6]-LH-RH itself, suggesting that an intact C terminus as well as an N terminus is necessary for the full expression of gonadotropin release.