Discovery of kynurenines containing oligopeptides as potent opioid receptor agonists

Edina Szűcs, Azzurra Stefanucci, Marilisa Pia Dimmito, Ferenc Zádor, Stefano Pieretti, Gokhan Zengin, László Vécsei, Sándor Benyhe, Marianna Nalli, Adriano Mollica

Research output: Contribution to journalArticle

Abstract

Kynurenine (kyn) and kynurenic acid (kyna) are well-defined metabolites of tryptophan catabolism collectively known as “kynurenines”, which exert regulatory functions in host-microbiome signaling, immune cell response, and neuronal excitability. Kynurenine containing peptides endowed with opioid receptor activity have been isolated from natural organisms; thus, in this work, novel opioid peptide analogs incorporating L-kynurenine (L-kyn) and kynurenic acid (kyna) in place of native amino acids have been designed and synthesized with the aim to investigate the biological effect of these modifications. The kyna-containing peptide (KA1) binds selectively the μ-opioid receptor with a Ki = 1.08 ± 0.26 (selectivity ratio μ/δ/ĸ = 1:514:10000), while the L-kyn-containing peptide (K6) shows a mixed binding affinity for μ, δ, and ĸ-opioid receptors, with efficacy and potency (Emax = 209.7 + 3.4%; LogEC50 = −5.984 + 0.054) higher than those of the reference compound DAMGO. This novel oligopeptide exhibits a strong antinociceptive effect after i.c.v. and s.c. administrations in in vivo tests, according to good stability in human plasma (t1/2 = 47 min).

Original languageEnglish
Article number284
JournalBiomolecules
Volume10
Issue number2
DOIs
Publication statusPublished - Feb 2020

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Keywords

  • Binding affinity
  • G-protein activation
  • Kynurenines
  • Peptides
  • Pharmacophore
  • μ-opioid receptor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Szűcs, E., Stefanucci, A., Dimmito, M. P., Zádor, F., Pieretti, S., Zengin, G., Vécsei, L., Benyhe, S., Nalli, M., & Mollica, A. (2020). Discovery of kynurenines containing oligopeptides as potent opioid receptor agonists. Biomolecules, 10(2), [284]. https://doi.org/10.3390/biom10020284