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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	ACS Medicinal Chemistry Letters
Vol/bind	5
Udgave nummer	4
Sider (fra-til)	352-357
Antal sider	6
ISSN	1948-5875
DOI	https://doi.org/10.1021/ml4004765
Status	Udgivet - 10 apr. 2014

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10.1021/ml4004765

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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",

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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

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