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

Research output: Contribution to journalJournal articlepeer-review

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In Vitro Membrane Permeation Studies and in Vivo Antinociception of Glycosylated Dmt(1)-DALDA Analogues. / Ballet, Steven; Betti, Cecilia; Novoa, Alexandre; Tömböly, Csaba; Nielsen, Carsten Uhd; 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 journalJournal articlepeer-review

Harvard

Ballet, S, Betti, C, Novoa, A, Tömböly, C, Nielsen, CU, 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 Dmt(1)-DALDA Analogues', ACS Medicinal Chemistry Letters, vol. 5, no. 4, pp. 352-357. https://doi.org/10.1021/ml4004765

APA

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

Vancouver

Ballet S, Betti C, Novoa A, Tömböly C, Nielsen CU, Helms HC et al. In Vitro Membrane Permeation Studies and in Vivo Antinociception of Glycosylated Dmt(1)-DALDA Analogues. ACS Medicinal Chemistry Letters. 2014 Apr 10;5(4):352-357. https://doi.org/10.1021/ml4004765

Author

Ballet, Steven ; Betti, Cecilia ; Novoa, Alexandre ; Tömböly, Csaba ; Nielsen, Carsten Uhd ; 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 Dmt(1)-DALDA Analogues. In: ACS Medicinal Chemistry Letters. 2014 ; Vol. 5, No. 4. pp. 352-357.

Bibtex

@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",

}

RIS

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

VL - 5

SP - 352

EP - 357

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

IS - 4

ER -

ID: 112718768