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ACS Med Chem Lett. 2014 Apr 10;5(4):352-357.

In Vitro Membrane Permeation Studies and in Vivo Antinociception of Glycosylated Dmt1-DALDA Analogues.

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Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.
Laboratory of Chemical Biology, Biological Research Centre of the Hungarian Academy of Sciences, Temesvári, krt. 62, H-6726 Szeged, Hungary.
The Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland.
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Montreal, QC H2W 1R7, Canada.
Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland ; Tufts University School of Medicine, Boston, Massachusetts 02111, United States.


In this study the μ opioid receptor (MOR) ligands DALDA (Tyr-d-Arg-Phe-Lys-NH2) and Dmt1-DALDA (Dmt-d-Arg-Phe-Lys-NH2, Dmt = 2',6'-dimethyltyrosine) were glycosylated at the N- or C-terminus. Subsequently, the modified peptides were subjected to in vitro and in vivo evaluation. In contrast to the N-terminally modified peptide (3), all peptide analogues derivatized at the C-terminus (4-7) proved to possess high affinity and agonist potency at both MOR and DOR (δ opioid receptor). Results of the Caco-2 monolayer permeation, as well as in vitro blood-brain barrier model experiments, showed that, in the case of compound 4, the glycosylation only slightly diminished the lumen-to-blood and blood-to-lumen transport. Altogether, these experiments were indicative of transcellular transport but not active transport. In vivo assays demonstrated that the peptides were capable of (i) crossing the blood-brain barrier (BBB) and (ii) activating both the spinal ascending as well as the descending opioid pathways, as determined by the tail-flick and hot-plate assays, respectively. In contrast to the highly selective MOR agonist Dmt1-DALDA 1, compounds 4-7 are mixed MOR/DOR agonists, expected to produce reduced opioid-related side effects.


Dmt1-DALDA; Opioid peptides; glycosylation; in vivo antinociception

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