In Vitro Membrane Permeation Studies and in Vivo Antinociception of Glycosylated Dmt1-DALDA Analogues: IF 3.12

Steven Ballet, Cecilia Betti, Alexandre Novoa, Csaba Tömböly, Christian Helms, Anna Lesniak, Patrycja Kleczkowska, Nga N. Chung, A.w. Lipkowski, Birger Brodin, Dirk Tourwe, P.w. Schiller

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Abstract



In this study the ? 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 (? 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.
Original languageEnglish
Pages (from-to)352-357
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume5
Issue number4
Publication statusPublished - 2014

Keywords

  • Opioid peptides
  • glycosylation
  • in vivo antinociception
  • DMt1-DALDA

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