In vitro membrane permeation studies and in vivo antinociception of glycosylated Dmt1-DALDA analogues

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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 Dmt 1-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
DOIs
Publication statusPublished - Apr 10 2014

Fingerprint

Permeation
Membranes
Peptides
Opioid Receptors
Blood-Brain Barrier
Opioid Analgesics
Assays
Blood
Glycosylation
Transcytosis
Active Biological Transport
Monolayers
Experiments
Ligands
tyrosyl-arginyl-phenylalanyl-lysinamide
In Vitro Techniques

Keywords

  • glycosylation
  • in vivo antinociception
  • Opioid peptides

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

Cite this

In vitro membrane permeation studies and in vivo antinociception of glycosylated Dmt1-DALDA analogues. / Ballet, Steven; Betti, Cecilia; Novoa, Alexandre; Tömböly, C.; Uhd Nielsen, Carsten; Helms, Hans Christian; Lesniak, Anna; Kleczkowska, Patrycja; Chung, Nga N.; Lipkowski, Andrzej W.; Brodin, Birger; Tourwé, Dirk; Schiller, Peter W.

In: ACS Medicinal Chemistry Letters, Vol. 5, No. 4, 10.04.2014, p. 352-357.

Research output: Contribution to journalArticle

Ballet, S, Betti, C, Novoa, A, Tömböly, C, Uhd Nielsen, C, Helms, HC, Lesniak, A, Kleczkowska, P, Chung, NN, Lipkowski, AW, Brodin, B, Tourwé, D & Schiller, PW 2014, 'In vitro membrane permeation studies and in vivo antinociception of glycosylated Dmt1-DALDA analogues', ACS Medicinal Chemistry Letters, vol. 5, no. 4, pp. 352-357. https://doi.org/10.1021/ml4004765
Ballet, Steven ; Betti, Cecilia ; Novoa, Alexandre ; Tömböly, C. ; Uhd Nielsen, Carsten ; Helms, Hans Christian ; Lesniak, Anna ; Kleczkowska, Patrycja ; Chung, Nga N. ; Lipkowski, Andrzej W. ; Brodin, Birger ; Tourwé, Dirk ; Schiller, Peter W. / In vitro membrane permeation studies and in vivo antinociception of glycosylated Dmt1-DALDA analogues. In: ACS Medicinal Chemistry Letters. 2014 ; Vol. 5, No. 4. pp. 352-357.
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AU - Uhd Nielsen, Carsten

AU - Helms, Hans Christian

AU - Lesniak, Anna

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AU - Chung, Nga N.

AU - Lipkowski, Andrzej W.

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