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Discovery of kynurenines containing oligopeptides as potent opioid receptor agonists
(MDPI AG, 2020) Szucs, Edina; Stefanucci, Azzurra; Dimmito, Marilisa Pia; Zádor, Ferenc; Pieretti, Stefano; Zengin, Gökhan; Vécsei, László
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 ?-opioid receptor with a Ki = 1.08 ± 0.26 (selectivity ratio ?/?/? = 1:514:10000), while the L-kyn-containing peptide (K6) shows a mixed binding affinity for ?, ?, and ?-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 by the authors. Licensee MDPI, Basel, Switzerland.