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Open AccessArticle

Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists

Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62., H-6726 Szeged, Hungary
Doctoral School of Theoretical Medicine, Faculty of Medicine, University of Szeged, Dómtér 10, H-6720 Szeged, Hungary
Department of Pharmacy, University of Chieti-Pescara “G. d’Annunzio”, Via dei Vestini 31, 66100 Chieti, Italy
National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
Department of Biology, Science Faculty, Selcuk University, 42250 Konya, Turkey
MTA-SZTE Neuroscience Research Group, Department of Neurology, Interdisciplinary Excellence Centre, Faculty of Medicine, University of Szeged, H-6725 Szeged, Hungary
Laboratory affiliated with the Institute Pasteur Italy-Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185 Roma, Italy
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(2), 284; (registering DOI)
Received: 27 December 2019 / Revised: 3 February 2020 / Accepted: 6 February 2020 / Published: 12 February 2020
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 m-opioid receptor with a Ki = 1.08 ± 0.26 (selectivity ratio m/d/k = 1:514:10000), while the L-kyn-containing peptide (K6) shows a mixed binding affinity for m, d, and k-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).
Keywords: peptides; kynurenines; binding affinity; μ-opioid receptor; pharmacophore; G-protein activation peptides; kynurenines; binding affinity; μ-opioid receptor; pharmacophore; G-protein activation
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MDPI and ACS Style

Szűcs, E.; Stefanucci, A.; Dimmito, M.P.; Zádor, F.; Pieretti, S.; Zengin, G.; Vécsei, L.; Benyhe, S.; Nalli, M.; Mollica, A. Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists. Biomolecules 2020, 10, 284.

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