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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.

Author information

1
Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.
2
Laboratory of Chemical Biology, Biological Research Centre of the Hungarian Academy of Sciences, Temesvári, krt. 62, H-6726 Szeged, Hungary.
3
The Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
4
Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland.
5
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Montreal, QC H2W 1R7, Canada.
6
Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland ; Tufts University School of Medicine, Boston, Massachusetts 02111, United States.

Abstract

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.

KEYWORDS:

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

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