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

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

doi:10.1021/ml4004765

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

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

9 Citations (Scopus)

Abstract

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 language	English
Journal	ACS Medicinal Chemistry Letters
Volume	5
Issue number	4
Pages (from-to)	352-357
Number of pages	6
ISSN	1948-5875
DOIs	https://doi.org/10.1021/ml4004765
Publication status	Published - 10 Apr 2014

Access to Document

10.1021/ml4004765

Cite this

Ballet, S., Betti, C., Novoa, A., Tömböly, C., Nielsen, C. U., Helms, H. C., Lesniak, A., Kleczkowska, P., Chung, N. N., Lipkowski, A. W., Brodin, B., Tourwé, D., & Schiller, P. W. (2014). In Vitro Membrane Permeation Studies and in Vivo Antinociception of Glycosylated Dmt(1)-DALDA Analogues. ACS Medicinal Chemistry Letters, 5(4), 352-357. https://doi.org/10.1021/ml4004765

@article{25586c033ef141a9b40ca023dd971018,

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

abstract = "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.",

author = "Steven Ballet and Cecilia Betti and Alexandre Novoa and Csaba T{\"o}mb{\"o}ly and Nielsen, {Carsten Uhd} and Helms, {Hans Christian} and Anna Lesniak and Patrycja Kleczkowska and Chung, {Nga N} and Lipkowski, {Andrzej W} and Birger Brodin and Dirk Tourw{\'e} and Schiller, {Peter W}",

year = "2014",

month = apr,

day = "10",

doi = "10.1021/ml4004765",

language = "English",

volume = "5",

pages = "352--357",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

publisher = "American Chemical Society",

number = "4",

}

TY - JOUR

T1 - In Vitro Membrane Permeation Studies and in Vivo Antinociception of Glycosylated Dmt(1)-DALDA Analogues

AU - Ballet, Steven

AU - Betti, Cecilia

AU - Novoa, Alexandre

AU - Tömböly, Csaba

AU - Nielsen, Carsten Uhd

AU - Helms, Hans Christian

AU - Lesniak, Anna

AU - Kleczkowska, Patrycja

AU - Chung, Nga N

AU - Lipkowski, Andrzej W

AU - Brodin, Birger

AU - Tourwé, Dirk

AU - Schiller, Peter W

PY - 2014/4/10

Y1 - 2014/4/10

N2 - 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.

AB - 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.

U2 - 10.1021/ml4004765

DO - 10.1021/ml4004765

M3 - Journal article

C2 - 24839540

SN - 1948-5875

VL - 5

SP - 352

EP - 357

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 4

ER -

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

Abstract

Access to Document

Fingerprint

Cite this