Effect of reductive alkylation of lysine in positions 6 and/or 8 on the histamine-releasing activity of luteinizing hormone-releasing hormone antagonists.

The solid-phase reductive alkylation of the Lys side chain in positions 6 (D) and 8 (L) and position 8 alone of the LH-RH antagonist [N-Ac-D-Nal,D-Ph2,3,D-Arg6,Phe7,D-Ala10]LH-RH was investigated in an attempt to reduce the histamine-releasing activity inherent to most potent antagonists while retaining high antiovulatory activity. The protected parent analogues were prepared by conventional solid-phase peptide synthesis. After selective removal of the Lys Fmoc side chain protection, the resin-bound peptides were readily and conveniently alkylated at the epsilon amino groups with various aldehydes and ketones in the presence of NaBH3CN. The analogues were then cleaved from the resin with simultaneous deprotection by anhydrous hydrogen fluoride and purified to homogeneity in two stages: gel permeation followed by preparative reversed-phase liquid chromatography. The analogues were assayed in standard rat antiovulatory and in vitro histamine-release assays.