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 (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).

Discovery of Kynurenines containing oligopeptides as potent opioid receptor agonists / Sz ˝ucs, Edina; Stefanucci, Azzurra; Pia Dimmito, Marilisa; Zádor, Ferenc; Pieretti, Stefano; Zengin, Gokhan; Vécsei, László; Benyhe, Sándor; Nalli, Marianna; Mollica, Adriano. - In: BIOMOLECULES. - ISSN 2218-273X. - 10:2(2020). [10.3390/biom10020284]

Discovery of Kynurenines containing oligopeptides as potent opioid receptor agonists

Azzurra Stefanucci
;
Stefano Pieretti;Marianna Nalli;Adriano Mollica
2020

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/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 (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).
2020
peptides; kynurenines; binding affinity; μ-opioid receptor; pharmacophore; G-protein activation
01 Pubblicazione su rivista::01a Articolo in rivista
Discovery of Kynurenines containing oligopeptides as potent opioid receptor agonists / Sz ˝ucs, Edina; Stefanucci, Azzurra; Pia Dimmito, Marilisa; Zádor, Ferenc; Pieretti, Stefano; Zengin, Gokhan; Vécsei, László; Benyhe, Sándor; Nalli, Marianna; Mollica, Adriano. - In: BIOMOLECULES. - ISSN 2218-273X. - 10:2(2020). [10.3390/biom10020284]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1454619
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