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 beta-O-glycosidically linked to a Thr4 or Thr7 side chain. Their activities were determined in binding studies based on displacement of mu- and delta-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 delta- or mu-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.
Tomatis
R
R
Department of Pharmaceutical Sciences, University of Ferrara, Italy.
Marastoni
M
M
Balboni
G
G
Guerrini
R
R
Capasso
A
A
Sorrentino
L
L
Santagada
V
V
Caliendo
G
G
Lazarus
L H
LH
Salvadori
S
S
D000595:Amino Acid Sequence; D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000378:metabolism; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007583:Jejunum; D007700:Kinetics; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D018847:Opioid Peptides; D010146:Pain; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism
D000701:Analgesics, Opioid; D004745:Enkephalins; D006020:Glycopeptides; D007202:Indicators and Reagents; D009842:Oligopeptides; D018847:Opioid Peptides; D011957:Receptors, Opioid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C059567:deltorphin; C030058:dermorphin