A chimeric opioid peptide with mixed mu agonist/delta antagonist properties.
There is evidence to indicate that opioid compounds with mixed mu agonist/delta antagonist properties are analgesics with low propensity to produce tolerance and physical dependence. A chimeric peptide containing the potent and selective mu agonist H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA) (Dmt=2',6'-dimethyltyrosine) and the potent and selective delta antagonist H-Tyr-TicPsi[CH2-NH]Cha-Phe-OH (TICP[Psi]) (Cha=cyclohexylalanine), connected 'tail-to-tail' via a short linker, was synthesized using a combination of solid-phase and solution techniques. The resulting peptide, H-Dmt-->D-Arg-->Phe-->Lys-NH-CH2-CH2-NH-Phe<--Cha[NH-CH2]PsiTic<--Tyr-H, showed the expected mu agonist/delta antagonist profile in the guinea-pig ileum and mouse vas deferens assays. Its mu and delta receptor binding affinities were in the low nanomolar range, as determined in rat brain membrane binding assays.
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7.
G
G
Weltrowska
C
C
Lemieux
N N
NN
Chung
P W
PW
Schiller
D000449:Aldehyde Reductase / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D001681:Biological Assay; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D051379:Mice; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018847:Opioid Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism
C492090:N(1)-(2',6'-dimethyltyrosyl-arginyl-phenylalanyl-lysyl)-N(2)-(tyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-psi(CH2NH)-cyclohexylalanyl-phenylalanyl)ethylenediamine; D009842:Oligopeptides; D018847:Opioid Peptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D017480:Receptors, sigma; C066498:Akr1b7 protein, mouse; D000449:Aldehyde Reductase