In Vitro Membrane Permeation Studies and in Vivo Antinociception of Glycosylated Dmt(1)-DALDA Analogues

In this study the mu opioid receptor (MOR) ligands DALDA (Tyr-D-Arg-Phe-Lys-NH2) and Dmt(1)-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 contr...

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Published inACS medicinal chemistry letters Vol. 5; no. 4; pp. 352 - 357
Main Authors Ballet, Steven, Betti, Cecilia, Novoa, Alexandre, Toemboely, Csaba, Nielsen, Carsten Uhd, Helms, Hans Christian, Lesniak, Anna, Kleczkowska, Patrycja, Chung, Nga N., Lipkowski, Andrzej W., Brodin, Birger, Tourwe, Dirk, Schiller, Peter W.
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 10.04.2014
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
OPIOID ACTIVITY
TRANSPORT
PERMEABILITY
in vivo antinociception
Opioid peptides
glycosylation
MANNITOL
Dmt-DALDA
BLOOD-BRAIN-BARRIER
BIOAVAILABILITY
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Summary:In this study the mu opioid receptor (MOR) ligands DALDA (Tyr-D-Arg-Phe-Lys-NH2) and Dmt(1)-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 (delta 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 Dmt(1)-DALDA 1, compounds 4-7 are mixed MOR/DOR agonists, expected to produce reduced opioid-related side effects.
Bibliography:NIH RePORTER
ISSN:1948-5875
1948-5875
DOI:10.1021/ml4004765