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Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists
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 rec...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072329/ https://www.ncbi.nlm.nih.gov/pubmed/32059524 http://dx.doi.org/10.3390/biom10020284 |
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author | Szűcs, Edina Stefanucci, Azzurra Dimmito, Marilisa Pia Zádor, Ferenc Pieretti, Stefano Zengin, Gokhan Vécsei, László Benyhe, Sándor Nalli, Marianna Mollica, Adriano |
author_facet | Szűcs, Edina Stefanucci, Azzurra Dimmito, Marilisa Pia Zádor, Ferenc Pieretti, Stefano Zengin, Gokhan Vécsei, László Benyhe, Sándor Nalli, Marianna Mollica, Adriano |
author_sort | Szűcs, Edina |
collection | PubMed |
description | 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/κ = 1:514:10,000), while the L-kyn-containing peptide (K6) shows a mixed binding affinity for μ, δ, and κ-opioid receptors, with efficacy and potency (E(max) = 209.7 + 3.4%; LogEC(50) = −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 (t(1/2) = 47 min). |
format | Online Article Text |
id | pubmed-7072329 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-70723292020-03-19 Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists Szűcs, Edina Stefanucci, Azzurra Dimmito, Marilisa Pia Zádor, Ferenc Pieretti, Stefano Zengin, Gokhan Vécsei, László Benyhe, Sándor Nalli, Marianna Mollica, Adriano Biomolecules Article 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/κ = 1:514:10,000), while the L-kyn-containing peptide (K6) shows a mixed binding affinity for μ, δ, and κ-opioid receptors, with efficacy and potency (E(max) = 209.7 + 3.4%; LogEC(50) = −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 (t(1/2) = 47 min). MDPI 2020-02-12 /pmc/articles/PMC7072329/ /pubmed/32059524 http://dx.doi.org/10.3390/biom10020284 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Szűcs, Edina Stefanucci, Azzurra Dimmito, Marilisa Pia Zádor, Ferenc Pieretti, Stefano Zengin, Gokhan Vécsei, László Benyhe, Sándor Nalli, Marianna Mollica, Adriano Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists |
title | Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists |
title_full | Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists |
title_fullStr | Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists |
title_full_unstemmed | Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists |
title_short | Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists |
title_sort | discovery of kynurenines containing oligopeptides as potent opioid receptor agonists |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072329/ https://www.ncbi.nlm.nih.gov/pubmed/32059524 http://dx.doi.org/10.3390/biom10020284 |
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