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)-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.