Novel glycosylated [Lys(7)]-dermorphin analogues: synthesis, biological activity and conformational investigations.
Syntheses of the [Lys(7)]- and [Hyp(6),Lys(7)]-dermorphin analogues in which either Tyr(5) or Hyp(6) are O-glucosylated are described. For comparison, the carbohydrate-free peptides have also been prepared. Structural investigations by FT-IR and CD measurements were carried out on the synthetic analogues and some preliminary pharmacological experiments were also performed. The biological potency of the glucosylated analogues was compared with that of the micro-opioid receptor agonist dermorphin in GPI preparations. Glucosylation of either Tyr(5) or Hyp(6) reduces the potency of both [Lys(7)]-dermorphin and [Hyp(6),Lys(7)]-dermorphin. The effect induced by the Tyr(5) glucosylation is quite strong and the potency of both peptides is reduced by about 150 times. A similar but less dramatic effect is induced by the glucosylation of the Hyp(6) residue, and the potency of the parent peptide is reduced by about 15 times. The presence of acetyl groups on the sugar hydroxyl functions further reduces the agonistic potency of the glucosylated analogues. The analgesic potency of [Hyp(6),Lys(7)]-, [Hyp(betaGlc)(6),Lys(7)]- and [Tyr(betaGlc)(5),Lys(7)]-dermorphin were also tested in vivo by the tail-flick test. The glucosylated hydroxyproline-containing analogue is 8-10 times less active than the parent peptide, but its analgesic effect lasts significantly longer.
Biondi
Laura
L
Department of Chemical Sciences, University of Padova, Institute of Biomolecular Chemistry, C.N.R., Section of Padova, via Marzolo, 1-35131 Padova, Italy.
Filira
Fernando
F
Giannini
Elisa
E
Gobbo
Marina
M
Lattanzi
Roberta
R
Negri
Lucia
L
Rocchi
Raniero
R
D000595:Amino Acid Sequence; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002942:Circular Dichroism; D006020:Glycopeptides / Q000737:chemistry* / Q000494:pharmacology; D006031:Glycosylation; D006168:Guinea Pigs; D008297:Male; D009197:Myenteric Plexus / Q000187:drug effects; D018847:Opioid Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010147:Pain Measurement; D051381:Rats; D017450:Receptors, Opioid, mu / Q000819:agonists; D013055:Spectrophotometry, Infrared; D017550:Spectroscopy, Fourier Transform Infrared
D000700:Analgesics; D006020:Glycopeptides; D018847:Opioid Peptides; D017450:Receptors, Opioid, mu; C030058:dermorphin