Blood-brain transfer and antinociception of linear and cyclic N-methyl-guanidine and thiourea-enkephalins

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Blood-brain transfer and antinociception of linear and cyclic N-methyl-guanidine and thiourea-enkephalins. / Verbeken, Mathieu; Wynendaele, Evelien; Mauchauffee, Elodie; Bracke, Nathalie; Stalmans, Sofie; Bojnik, Engin; Benyhe, Sandor; Peremans, Kathelijne; Polis, Ingeborgh; Burvenich, Christian; Gjedde, Albert; Hernandez, Jean-Francois; De Spiegeleer, Bart.

In: Peptides, Vol. 63, 01.2015, p. 10-21.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Verbeken, M, Wynendaele, E, Mauchauffee, E, Bracke, N, Stalmans, S, Bojnik, E, Benyhe, S, Peremans, K, Polis, I, Burvenich, C, Gjedde, A, Hernandez, J-F & De Spiegeleer, B 2015, 'Blood-brain transfer and antinociception of linear and cyclic N-methyl-guanidine and thiourea-enkephalins', Peptides, vol. 63, pp. 10-21. https://doi.org/10.1016/j.peptides.2014.10.010

APA

Verbeken, M., Wynendaele, E., Mauchauffee, E., Bracke, N., Stalmans, S., Bojnik, E., Benyhe, S., Peremans, K., Polis, I., Burvenich, C., Gjedde, A., Hernandez, J-F., & De Spiegeleer, B. (2015). Blood-brain transfer and antinociception of linear and cyclic N-methyl-guanidine and thiourea-enkephalins. Peptides, 63, 10-21. https://doi.org/10.1016/j.peptides.2014.10.010

Vancouver

Verbeken M, Wynendaele E, Mauchauffee E, Bracke N, Stalmans S, Bojnik E et al. Blood-brain transfer and antinociception of linear and cyclic N-methyl-guanidine and thiourea-enkephalins. Peptides. 2015 Jan;63:10-21. https://doi.org/10.1016/j.peptides.2014.10.010

Author

Verbeken, Mathieu ; Wynendaele, Evelien ; Mauchauffee, Elodie ; Bracke, Nathalie ; Stalmans, Sofie ; Bojnik, Engin ; Benyhe, Sandor ; Peremans, Kathelijne ; Polis, Ingeborgh ; Burvenich, Christian ; Gjedde, Albert ; Hernandez, Jean-Francois ; De Spiegeleer, Bart. / Blood-brain transfer and antinociception of linear and cyclic N-methyl-guanidine and thiourea-enkephalins. In: Peptides. 2015 ; Vol. 63. pp. 10-21.

Bibtex

@article{948dfec5556243f9a78dd07fae383123,
title = "Blood-brain transfer and antinociception of linear and cyclic N-methyl-guanidine and thiourea-enkephalins",
abstract = "Enkephalins are active in regulation of nociception in the body and are key in development of new synthetic peptide analogs that target centrally located opioid receptors. In this study, we investigated the in vivo blood–brain barrier (BBB) penetration behavior and antinociceptive activity of two cyclic enkephalin analogs with a thiourea (CycS) or a N-methyl-guanidine bridge (CycNMe), and their linear counterparts (LinS and LinNMe) in mice, as well as their in vitro metabolic stability. 125I-LinS had the highest blood–brain clearance (K1 = 3.46 μL/g min), followed by 125I-LinNMe, 125I-CycNMe, and 125I-CycS (K1 = 1.64, 0.31, and 0.11 μL/g min, respectively). Also, these peptides had a high metabolic stability (t1/2 > 1 h) in mouse serum and brain homogenate, and half-inhibition constant (Ki) values in the nanomolar range with predominantly μ-opioid receptor selectivity. The positively charged NMe-enkephalins showed a higher antinociceptive activity (LinNMe: 298% and CycNMe: 205%), expressed as molar-dose normalized area under the curve (AUC) relative to morphine, than the neutral S-enkephalins (CycS: 122% and LinS: 130%).",
keywords = "Blood-brain barrier (BBB) transport (influx/efflux), Antinociceptive activity, Linear/cyclic enkephalin analogsIn, vivo mouse modelsa",
author = "Mathieu Verbeken and Evelien Wynendaele and Elodie Mauchauffee and Nathalie Bracke and Sofie Stalmans and Engin Bojnik and Sandor Benyhe and Kathelijne Peremans and Ingeborgh Polis and Christian Burvenich and Albert Gjedde and Jean-Francois Hernandez and {De Spiegeleer}, Bart",
year = "2015",
month = jan,
doi = "10.1016/j.peptides.2014.10.010",
language = "English",
volume = "63",
pages = "10--21",
journal = "Peptides",
issn = "0196-9781",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Blood-brain transfer and antinociception of linear and cyclic N-methyl-guanidine and thiourea-enkephalins

AU - Verbeken, Mathieu

AU - Wynendaele, Evelien

AU - Mauchauffee, Elodie

AU - Bracke, Nathalie

AU - Stalmans, Sofie

AU - Bojnik, Engin

AU - Benyhe, Sandor

AU - Peremans, Kathelijne

AU - Polis, Ingeborgh

AU - Burvenich, Christian

AU - Gjedde, Albert

AU - Hernandez, Jean-Francois

AU - De Spiegeleer, Bart

PY - 2015/1

Y1 - 2015/1

N2 - Enkephalins are active in regulation of nociception in the body and are key in development of new synthetic peptide analogs that target centrally located opioid receptors. In this study, we investigated the in vivo blood–brain barrier (BBB) penetration behavior and antinociceptive activity of two cyclic enkephalin analogs with a thiourea (CycS) or a N-methyl-guanidine bridge (CycNMe), and their linear counterparts (LinS and LinNMe) in mice, as well as their in vitro metabolic stability. 125I-LinS had the highest blood–brain clearance (K1 = 3.46 μL/g min), followed by 125I-LinNMe, 125I-CycNMe, and 125I-CycS (K1 = 1.64, 0.31, and 0.11 μL/g min, respectively). Also, these peptides had a high metabolic stability (t1/2 > 1 h) in mouse serum and brain homogenate, and half-inhibition constant (Ki) values in the nanomolar range with predominantly μ-opioid receptor selectivity. The positively charged NMe-enkephalins showed a higher antinociceptive activity (LinNMe: 298% and CycNMe: 205%), expressed as molar-dose normalized area under the curve (AUC) relative to morphine, than the neutral S-enkephalins (CycS: 122% and LinS: 130%).

AB - Enkephalins are active in regulation of nociception in the body and are key in development of new synthetic peptide analogs that target centrally located opioid receptors. In this study, we investigated the in vivo blood–brain barrier (BBB) penetration behavior and antinociceptive activity of two cyclic enkephalin analogs with a thiourea (CycS) or a N-methyl-guanidine bridge (CycNMe), and their linear counterparts (LinS and LinNMe) in mice, as well as their in vitro metabolic stability. 125I-LinS had the highest blood–brain clearance (K1 = 3.46 μL/g min), followed by 125I-LinNMe, 125I-CycNMe, and 125I-CycS (K1 = 1.64, 0.31, and 0.11 μL/g min, respectively). Also, these peptides had a high metabolic stability (t1/2 > 1 h) in mouse serum and brain homogenate, and half-inhibition constant (Ki) values in the nanomolar range with predominantly μ-opioid receptor selectivity. The positively charged NMe-enkephalins showed a higher antinociceptive activity (LinNMe: 298% and CycNMe: 205%), expressed as molar-dose normalized area under the curve (AUC) relative to morphine, than the neutral S-enkephalins (CycS: 122% and LinS: 130%).

KW - Blood-brain barrier (BBB) transport (influx/efflux)

KW - Antinociceptive activity

KW - Linear/cyclic enkephalin analogsIn

KW - vivo mouse modelsa

U2 - 10.1016/j.peptides.2014.10.010

DO - 10.1016/j.peptides.2014.10.010

M3 - Journal article

C2 - 25451468

VL - 63

SP - 10

EP - 21

JO - Peptides

JF - Peptides

SN - 0196-9781

ER -

ID: 160922631