Glycosylated Peptide Hormones: Pharmacological Properties and Conformational Studies of Analogs of [1-Desamino,8-D-arginine]vasopressin

Two analogues of the antidiuretic drug [1-desamino,8-D-arginine]vasopressin (DDAVP), which have a glycosylated serine at position 4, have been prepared by Fmoc solid phase peptide synthesis. The glycosylated analogues had significantly higher bioavailabilities than the nonglycosylated [D-Tyr2,Ser4]DDAVP and DDAVP on intraintestinal administration in rat. The improved bioavailability resulted from an increased absorption from the small intestine and most likely from an increased stability toward enzymatic degradation, whereas plasma clearance was either unaffected or slightly increased by the glycosylation. The glycosylated analogues displayed only very low agonistic and antagonistic activities at the vasopressin V2-receptor. Conformational studies performed by 1H NMR spectroscopy did not reveal any major influence from glycosylation on the conformation of the peptide backbone. The lack of receptor binding displayed by the analogues is therefore most likely explained by steric repulsion between the carbohydrate moiety and the vasopressin receptor which prevents receptor binding.