Synthesis and Pharmacological Activity of Deltorphin and Dermorphin-Related Glycopeptides

The solid phase procedure, based on the Fmoc chemistry, was used to prepare some opioid deltorphin (H-Tyr-d-Ala-Phe-Asp-Val-Val-Gly-NH2, DEL C) and dermorphin (H-Tyr-d-Ala-Phe-Gly-Tyr-Pro-Ser-NH2, DER) analogues in which a d-glucopyranosyl moiety is β-O-glycosidically linked to a Thr4 or Thr7 side c...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1997-08, Vol.40 (18), p.2948-2952
Main Authors: Tomatis, Roberto, Marastoni, Mauro, Balboni, Gianfranco, Guerrini, Remo, Capasso, Anna, Sorrentino, Ludovico, Santagada, Vincenzo, Caliendo, Giuseppe, Lazarus, Lawrence H, Salvadori, Severo
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Analgesics
Analgesics, Opioid - chemical synthesis
Analgesics, Opioid - chemistry
Analgesics, Opioid - pharmacology
Animals
Binding, Competitive
Biological and medical sciences
Enkephalin, Ala-MePhe-Gly
Enkephalins - metabolism
Glycopeptides - chemical synthesis
Glycopeptides - chemistry
Glycopeptides - pharmacology
Guinea Pigs
Ileum
In Vitro Techniques
Indicators and Reagents
Jejunum
Kinetics
Male
Medical sciences
Mice
Muscle Contraction - drug effects
Muscle, Smooth - drug effects
Muscle, Smooth - physiology
Neuropharmacology
Oligopeptides - chemical synthesis
Oligopeptides - pharmacology
Opioid Peptides
Pain
Pharmacology. Drug treatments
Rabbits
Rats
Rats, Sprague-Dawley
Receptors, Opioid - metabolism
Structure-Activity Relationship
Synaptosomes - metabolism
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Summary:The solid phase procedure, based on the Fmoc chemistry, was used to prepare some opioid deltorphin (H-Tyr-d-Ala-Phe-Asp-Val-Val-Gly-NH2, DEL C) and dermorphin (H-Tyr-d-Ala-Phe-Gly-Tyr-Pro-Ser-NH2, DER) analogues in which a d-glucopyranosyl moiety is β-O-glycosidically linked to a Thr4 or Thr7 side chain. Their activities were determined in binding studies based on displacement of μ- and δ-receptor selective radiolabels from rat brain membrane synaptosomes, in guinea pig ileum and rabbit jejenum bioassays, and, in vivo, by a mouse tail-flick test after intracerebroventricular (icv) and subcutaneous (sc) administrations. The glyco analogues modified at position 4 displayed low opioid properties, while Thr7-glycosylated peptides retained high δ- or μ-selectivity and remarkable activity in vivo. In particular, as systemic antinociceptive agents, the latter glucoside-bearing compounds were more potent than the parent unglycosylated peptide counterparts, showing a high blood to brain rate of influx which may be due to the glucose transporter GLUT-1.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm970119r