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 agonists elicit similar effects to strong opioids but with reduced side effects. In this work, 31 peptides the general sequence [Tyr/Dmt1,Xaa5]N/OFQ(1-13)-NH2 were synthesized pharmacologically characterized for their action at human recombinant receptors. best results in terms of NOP versus mu opioid potency obtained by substituting both Tyr1 Thr5 N-terminal portion N/OFQ(1-13)-NH2 noncanonical amino acid Dmt. [Dmt1,5]N/OFQ(1-13)-NH2 has been identified as most potent dual NOP/mu peptide agonist so far described. Experimental data have complemented silico studies shed light on molecular mechanisms which binds active form receptor. Finally, compound exerted antitussive an vivo model cough.