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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Steven Ballet
  • Cecilia Betti
  • Alexandre Novoa
  • Csaba Tömböly
  • Carsten Uhd Nielsen
  • Hans Christian Helms
  • Anna Lesniak
  • Patrycja Kleczkowska
  • Nga N Chung
  • Andrzej W Lipkowski
  • Larsen, Birger Brodin
  • Dirk Tourwé
  • Peter W Schiller

In this study the μ 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 (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 Dmt(1)-DALDA 1, compounds 4-7 are mixed MOR/DOR agonists, expected to produce reduced opioid-related side effects.

Original languageEnglish
JournalACS Medicinal Chemistry Letters
Issue number4
Pages (from-to)352-357
Number of pages6
Publication statusPublished - 10 Apr 2014

ID: 112718768