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

Mathieu Verbeken, Evelien Wynendaele, Elodie Mauchauffée, Nathalie Bracke, Sofie Stalmans, Engin Bojnik, S. Benyhe, Kathelijne Peremans, Ingeborgh Polis, Christian Burvenich, Albert Gjedde, Jean Franc¸ois Hernandez, Bart De Spiegeleer

Research output: Contribution to journalArticle

9 Citations (Scopus)

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%).

Original languageEnglish
Pages (from-to)10-21
Number of pages12
JournalPeptides
Volume63
DOIs
Publication statusPublished - 2015

Fingerprint

Methylguanidine
Thiourea
Enkephalins
Brain
Blood
Opioid Receptors
Peptides
Nociception
Blood-Brain Barrier
Morphine
Area Under Curve
Transfer (Psychology)
Serum

Keywords

  • Antinociceptive activity
  • Blood-brain barrier (BBB) transport
  • In vivo mouse models
  • Influx/efflux
  • Linear/cyclic enkephalin analogs

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Physiology
  • Cellular and Molecular Neuroscience

Cite this

Verbeken, M., Wynendaele, E., Mauchauffée, E., Bracke, N., Stalmans, S., Bojnik, E., ... 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

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

In: Peptides, Vol. 63, 2015, p. 10-21.

Research output: Contribution to journalArticle

Verbeken, M, Wynendaele, E, Mauchauffée, E, Bracke, N, Stalmans, S, Bojnik, E, Benyhe, S, Peremans, K, Polis, I, Burvenich, C, Gjedde, A, Hernandez, JF & 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
Verbeken, Mathieu ; Wynendaele, Evelien ; Mauchauffée, Elodie ; Bracke, Nathalie ; Stalmans, Sofie ; Bojnik, Engin ; Benyhe, S. ; Peremans, Kathelijne ; Polis, Ingeborgh ; Burvenich, Christian ; Gjedde, Albert ; Hernandez, Jean Franc¸ois ; 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.
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AU - Bracke, Nathalie

AU - Stalmans, Sofie

AU - Bojnik, Engin

AU - Benyhe, S.

AU - Peremans, Kathelijne

AU - Polis, Ingeborgh

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AU - Gjedde, Albert

AU - Hernandez, Jean Franc¸ois

AU - De Spiegeleer, Bart

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