title: Effect of the CH2NH and CH2NAc peptide bond isosteres on the antagonistic and histamine releasing activities of a luteinizing hormone-releasing hormone analogue.
abstract: The effect of the CH2NH and CH2NAc peptide bond isosteres on the antagonistic and histamine releasing activities of the LH-RH antagonist [N-Ac-D-Nal1,D-Phe2,3,D-Arg6,Phe7,D-Ala10] LH-RH was investigated. The moieties were introduced by facile, racemization-free solid-phase synthesis in an attempt to reduce the histamine releasing activity inherent to the most potent analogues while retaining high antiovulatory activity. The psi [CH2NH] isostere was incorporated at each CONH site with the exception of 8-9, which involves Pro, by reductive alkylation with a protected amino acid aldehyde in the presence of NaBH3CN during conventional solid-phase peptide synthesis. The psi [CH2NH] group was extremely resistant to derivatization and could only be partially acetylated to give psi [CH2NAc]. The analogues were 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. The isosteres caused a loss of the antiovulatory activity of the antagonist at the 50-microgram dose when incorporated at the positions 1-2, 2-3, 3-4, and 7-8. Incorporation at the other positions resulted in a less marked reduction in activity relative to the unmodified parent analogue. No significant effect was noted on the potent histamine releasing activity of the analogues.
authors: Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112.
authors: S J
authors: SJ
authors: Hocart
authors: M V
authors: MV
authors: Nekola
authors: D H
authors: DH
authors: Coy
mesh_terms: D000107:Acetylation; D000478:Alkylation; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D006860:Hydrogen Bonding; D008744:Methylamines; D008968:Molecular Conformation; D010060:Ovulation / Q000187:drug effects; D010455:Peptides; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
chemical_list: D008744:Methylamines; D010455:Peptides; D007987:Gonadotropin-Releasing Hormone