Szűcs, Edina and Stefanucci, Azzurra and Dimmito, Marilisa Pia and Zádor, Ferenc and Pieretti, Stefano and Vécsei, László and Benyhe, Sándor (2020) Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists. Biomolecules, 10 (2). ISSN 2218-273X
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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 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).
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| Additional Information: | Funding Agency and Grant Number: National Research, Development and Innovation Office (NKFI), Budapest, Hungary [GINOP 2.3.2-15-2016-00034]; Ministry of Human Capacities, Hungary [20391-3/2018/FEKUSTRAT] Funding text: This research was supported by the project GINOP 2.3.2-15-2016-00034, provided by National Research, Development and Innovation O ffice (NKFI), Budapest, Hungary, and the Ministry of Human Capacities, Hungary grant 20391-3/2018/FEKUSTRAT. Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged, H-6726, Hungary Doctoral School of Theoretical Medicine, Faculty of Medicine, University of Szeged, Dómtér 10, Szeged, H-6720, Hungary Department of Pharmacy, University of Chieti-Pescara “G. d’Annunzio”, Via dei Vestini 31, Chieti, 66100, Italy National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy Department of Biology, Science Faculty, Selcuk University, Konya, 42250, Turkey MTA-SZTE Neuroscience Research Group, Department of Neurology, Interdisciplinary Excellence Centre, Faculty of Medicine, University of Szeged, Szeged, H-6725, 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, Roma, I-00185, Italy Export Date: 20 April 2020 Correspondence Address: Stefanucci, A.; Department of Pharmacy, University of Chieti-Pescara “G. d’Annunzio”, Via dei Vestini 31, Italy; email: a.stefanucci@unich.it Funding details: 20391‐3/2018/FEKUSTRAT Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFI Funding text 1: Funding: This research was supported by the project GINOP 2.3.2‐15‐2016‐00034, provided by National Research, Development and Innovation Office (NKFI), Budapest, Hungary, and the Ministry of Human Capacities, Hungary grant 20391‐3/2018/FEKUSTRAT. |
| Uncontrolled Keywords: | PEPTIDES; binding affinity; Kynurenines; G-PROTEIN ACTIVATION; pharmacophore; μ-opioid receptor; |
| Subjects: | Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 29 Jan 2021 09:59 |
| Last Modified: | 29 Jan 2021 09:59 |
| URI: | http://real.mtak.hu/id/eprint/120213 |
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