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...

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Bibliographic Details
Main Authors: Szűcs Edina
Stefanucci Azzurra
Dimmito Marilisa Pia
Zádor Ferenc
Pieretti Stefano
Zengin Gokhan
Vécsei László
Benyhe Sándor
Nalli Marianna
Mollica Adriano
Format: Article
Published: 2020
Series:BIOMOLECULES 10 No. 2
doi:10.3390/biom10020284

mtmt:31181191
Online Access:http://publicatio.bibl.u-szeged.hu/18367
Description
Summary: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).
Physical Description:Azonosító: 284-Terjedelem: 18 p
ISSN:2218-273X