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).File | Dimensione | Formato | |
---|---|---|---|
Szűcs_Discovery_2020.pdf
accesso aperto
Tipologia:
Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza:
Creative commons
Dimensione
2.86 MB
Formato
Adobe PDF
|
2.86 MB | Adobe PDF |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.