Solid-phase synthesis of O-linked glycopeptide analogues of enkephalin

The synthesis of 18 N-alpha -FMOC-amino acid glycosides for solid-phase gly copeptide assembly is reported. The glycosides were synthesized either from the corresponding O'Donnell Schiff bases or from N-alpha -FMOC-amino prote cted serine or threonine and the appropriate glycosyl bromide using Hanessi an's modification of the Koenigs-Knorr reaction. Reaction rates of D-glycos yl bromides (e.g., acetobromoglucose) with the L- and D-forms of serine and threonine are distinctly different and can be rationalized in terms of the steric interactions within the two types of diastereomeric transition stat es for the D/L and D/D reactant pairs. The N-alpha -FMOC-protected glycosid es [monosaccharides Xyl, Glc, Gal, Man, GlcNAc, and GalNAc; disaccharides G al-beta (1-4)-Gle (lactose), Glc-beta-(1-4)-Glc (cellobiose), and Gal-alpha (1-6)-Glc (melibiose)] were incorporated into 22 enkephalin glycopeptide a nalogues. These peptide opiates bearing the pharmacophore H-Tyr-c[DCys-Gly- PheDCys]- were designed to probe the significance of the glycoside moiety a nd the carbohydrate-peptide linkage region in blood-brain barrier (BBB) tra nsport, opiate receptor binding, and analgesia.