Novel Mixed NOP/Opioid Receptor Peptide Agonists
Salvatore Pacifico, Valentina Albanese, Davide Illuminati, Erika Marzola, M. Fabbri, Federica Ferrari, Victor A.D. Holanda, Chiara Sturaro, Davide Malfacini, Chiara Ruzza, Claudio Trapella, Delia Preti, Ettore Lo Cascio, Alessandro Arcovito, S. Della Longa, Martina Marangoni, Davide Fattori, Romina Nassini, Girolamo Calò, Remo Guerrini
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/Dmt 1 ,Xaa 5 ]N/OFQ(1-13)-NH 2 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 Tyr 1 and Thr 5 at the N-terminal portion of N/OFQ(1-13)-NH 2 with the noncanonical amino acid Dmt. [Dmt 1,5 ]N/OFQ(1-13)-NH 2 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.