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, Sandor Benyhe, Kathelijne Peremans, Ingeborgh Polis, Christian Burvenich, Albert Gjedde, Jean Franҫois Hernandez, Bart De Spiegeleer

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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. 125 I-LinS had the highest blood-brain clearance (K 1 = 3.46 μL/g min), followed by 125 I-LinNMe, 125 I-CycNMe, and 125 I-CycS (K 1 = 1.64, 0.31, and 0.11 μL/g min, respectively). Also, these peptides had a high metabolic stability (t 1/2 > 1 h) in mouse serum and brain homogenate, and half-inhibition constant (K i ) 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 (US)
Pages (from-to)10-21
Number of pages12
StatePublished - Jan 2015


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

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Endocrinology
  • Cellular and Molecular Neuroscience


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