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- Title
Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists.
- Authors
Szűcs, Edina; Stefanucci, Azzurra; Dimmito, Marilisa Pia; Zádor, Ferenc; Pieretti, Stefano; Zengin, Gokhan; Vécsei, László; Benyhe, Sándor; Nalli, Marianna; Mollica, Adriano
- 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).
- Subjects
OPIOID receptors; OPIOID peptides; OLIGOPEPTIDES; AMINO acids; KYNURENINE; PLASMA stability; METABOLITES; IN vivo studies
- Publication
Biomolecules (2218-273X), 2020, Vol 10, Issue 2, p284
- ISSN
2218-273X
- Publication type
Article
- DOI
10.3390/biom10020284