1. Novel Mixed NOP/Opioid Receptor Peptide Agonists
- Author
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Erika Marzola, Chiara Ruzza, Davide Illuminati, Salvatore Pacifico, Delia Preti, Claudio Trapella, Davide Malfacini, Ettore Lo Cascio, Valentina Albanese, Martina Marangoni, Remo Guerrini, Alessandro Arcovito, Martina Fabbri, Davide Fattori, Victor A D Holanda, Romina Nassini, Chiara Sturaro, Girolamo Calò, Federica Ferrari, and Stefano Della Longa
- Subjects
Male ,Opiod receptors ,NOP, MOP, Nociceptin ,NOP ,Receptors, Opioid, mu ,Peptide ,Pharmacology ,01 natural sciences ,Nociceptin Receptor ,Opioid receptor ,Drug Discovery ,Receptors ,Receptor ,chemistry.chemical_classification ,Animals ,Binding Sites ,Cough ,Disease Models, Animal ,Guinea Pigs ,Humans ,Hydrophobic and Hydrophilic Interactions ,Molecular Dynamics Simulation ,Peptides ,Receptors, Opioid ,Recombinant Proteins ,Structure-Activity Relationship ,0303 health sciences ,Chemistry ,Nociceptin ,Nociceptin receptor ,Molecular Medicine ,μ-opioid receptor ,medicine.drug ,Agonist ,medicine.drug_class ,Opioid ,Article ,NO ,03 medical and health sciences ,medicine ,Settore BIO/10 - BIOCHIMICA ,030304 developmental biology ,MOP ,Animal ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,mu ,Disease Models - 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.
- Published
- 2021