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.

Pacifico, S., Albanese, V., Illuminati, D., Marzola, E., Fabbri, M., Ferrari, F., Holanda, V. A. D., Sturaro, C., Malfacini, D., Ruzza, C., Trapella, C., Preti, D., Lo Cascio, E., Arcovito, A., Della Longa, S., Marangoni, M., Fattori, D., Nassini, R., Calo, G., Guerrini, R., Novel Mixed NOP/Opioid Receptor Peptide Agonists, <<JOURNAL OF MEDICINAL CHEMISTRY>>, 2021; 64 (10): 6656-6669. [doi:10.1021/acs.jmedchem.0c02062] [http://hdl.handle.net/10807/181205]

Novel Mixed NOP/Opioid Receptor Peptide Agonists

Lo Cascio, Ettore;Arcovito, Alessandro;
2021

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.
2021
Inglese
Pacifico, S., Albanese, V., Illuminati, D., Marzola, E., Fabbri, M., Ferrari, F., Holanda, V. A. D., Sturaro, C., Malfacini, D., Ruzza, C., Trapella, C., Preti, D., Lo Cascio, E., Arcovito, A., Della Longa, S., Marangoni, M., Fattori, D., Nassini, R., Calo, G., Guerrini, R., Novel Mixed NOP/Opioid Receptor Peptide Agonists, <<JOURNAL OF MEDICINAL CHEMISTRY>>, 2021; 64 (10): 6656-6669. [doi:10.1021/acs.jmedchem.0c02062] [http://hdl.handle.net/10807/181205]
File in questo prodotto:
File Dimensione Formato  
2021_Pacifico_acs.jmedchem.pdf

accesso aperto

Tipologia file ?: Versione Editoriale (PDF)
Licenza: Creative commons
Dimensione 2.61 MB
Formato Adobe PDF
2.61 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/181205
Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus 9
  • ???jsp.display-item.citation.isi??? 8
social impact