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]vasopr essin (DDAVP), which have a glycosylated serine at position 4, have be en prepared by Fmoc solid phase peptide synthesis. The glycosylated an alogues had significantly higher bioavailabilities than the nonglycosy lated [D-Tyr(2),Ser(4)]DDAVP and DDAVP on intraintestinal administrati on in rat. The improved bioavailability resulted from an increased abs orption from the small intestine and most likely from an increased sta bility toward enzymatic degradation, whereas plasma clearance was eith er unaffected or slightly increased by the glycosylation. The glycosyl ated analogues displayed only very low agonistic and antagonistic acti vities at the vasopressin V-2-receptor. Conformational studies perform ed by H-1 NMR spectroscopy did not reveal any major influence from gly cosylation on the conformation of the peptide backbone. The lack of re ceptor binding displayed by the analogues is therefore most likely exp lained by steric repulsion between the carbohydrate moiety and the vas opressin receptor which prevents receptor binding.