Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists
Edina Szűcs,
Azzurra Stefanucci,
Marilisa Pia Dimmito,
Ferenc Zádor,
Stefano Pieretti,
Gokhan Zengin,
László Vécsei,
Sándor Benyhe,
Marianna Nalli,
Adriano Mollica
Affiliations
Edina Szűcs
Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62., H-6726 Szeged, Hungary
Azzurra Stefanucci
Department of Pharmacy, University of Chieti-Pescara “G. d’Annunzio”, Via dei Vestini 31, 66100 Chieti, Italy
Marilisa Pia Dimmito
Department of Pharmacy, University of Chieti-Pescara “G. d’Annunzio”, Via dei Vestini 31, 66100 Chieti, Italy
Ferenc Zádor
Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62., H-6726 Szeged, Hungary
Stefano Pieretti
National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
Gokhan Zengin
Department of Biology, Science Faculty, Selcuk University, 42250 Konya, Turkey
László Vécsei
MTA-SZTE Neuroscience Research Group, Department of Neurology, Interdisciplinary Excellence Centre, Faculty of Medicine, University of Szeged, H-6725 Szeged, Hungary
Sándor Benyhe
Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62., H-6726 Szeged, Hungary
Marianna Nalli
Laboratory affiliated with the Institute Pasteur Italy-Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185 Roma, Italy
Adriano Mollica
Department of Pharmacy, University of Chieti-Pescara “G. d’Annunzio”, Via dei Vestini 31, 66100 Chieti, Italy
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).
