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Open AccessArticle

Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists

1
Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62., H-6726 Szeged, Hungary
2
Doctoral School of Theoretical Medicine, Faculty of Medicine, University of Szeged, Dómtér 10, H-6720 Szeged, Hungary
3
Department of Pharmacy, University of Chieti-Pescara “G. d’Annunzio”, Via dei Vestini 31, 66100 Chieti, Italy
4
National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
5
Department of Biology, Science Faculty, Selcuk University, 42250 Konya, Turkey
6
MTA-SZTE Neuroscience Research Group, Department of Neurology, Interdisciplinary Excellence Centre, Faculty of Medicine, University of Szeged, H-6725 Szeged, Hungary
7
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; https://doi.org/10.3390/biom10020284 (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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