Novel Mixed NOP/Opioid Receptor Peptide Agonists

Alessandro Arcovito, Ettore Lo Cascio, Salvatore Pacifico, Valentina Albanese, Davide Illuminati, Erika Marzola, Martina Fabbri, Federica Ferrari, Victor A D Holanda, Chiara Sturaro, Davide Malfacini, Chiara Ruzza, Claudio Trapella, Delia Preti, Stefano Della Longa, Martina Marangoni, Davide Fattori, Romina Nassini, Girolamo Calò, Remo Guerrini

Risultato della ricerca: Contributo in rivistaArticolo in rivista

Abstract

The nociceptin/orphanin FQ (N/OFQ)/N/OFQ receptor (NOP) system controls different biological functions including pain and cough reflex. Mixed NOP/opioid receptor agonists elicit similar effects to strong opioids but with reduced side effects. In this work, 31 peptides with the general sequence [Tyr/Dmt1,Xaa5]N/OFQ(1-13)-NH2 were synthesized and pharmacologically characterized for their action at human recombinant NOP/opioid receptors. The best results in terms of NOP versus mu opioid receptor potency were obtained by substituting both Tyr1 and Thr5 at the N-terminal portion of N/OFQ(1-13)-NH2 with the noncanonical amino acid Dmt. [Dmt1,5]N/OFQ(1-13)-NH2 has been identified as the most potent dual NOP/mu receptor peptide agonist so far described. Experimental data have been complemented by in silico studies to shed light on the molecular mechanisms by which the peptide binds the active form of the mu receptor. Finally, the compound exerted antitussive effects in an in vivo model of cough.
Lingua originaleEnglish
pagine (da-a)6656-6669
Numero di pagine14
RivistaJournal of Medicinal Chemistry
Volume64
DOI
Stato di pubblicazionePubblicato - 2021

Keywords

  • NOP, MOP, Nociceptin
  • Opiod receptors

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