Novel Mixed NOP/Opioid Receptor Peptide Agonists

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)-NH2were 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 Tyr1and Thr5at the N-terminal portion of N/OFQ(1-13)-NH2with the noncanonical amino acid Dmt. [Dmt1,5]N/OFQ(1-13)-NH2has been identified as the most potent dual NOP/mu receptor peptide agonist so far described. Experimental data have been complemented by in silicostudies 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 vivomodel of cough.