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. 2021 May 27;64(10):6656-6669.
doi: 10.1021/acs.jmedchem.0c02062. Epub 2021 May 17.

Novel Mixed NOP/Opioid Receptor Peptide Agonists

Salvatore Pacifico  1 , Valentina Albanese  1 , Davide Illuminati  1 , Erika Marzola  1 , Martina Fabbri  1 , Federica Ferrari  2 , Victor A D Holanda  2 , Chiara Sturaro  2 , Davide Malfacini  3 , Chiara Ruzza  2   4 , Claudio Trapella  1   4 , Delia Preti  1 , Ettore Lo Cascio  5 , Alessandro Arcovito  5   6 , Stefano Della Longa  7 , Martina Marangoni  8 , Davide Fattori  8 , Romina Nassini  8 , Girolamo Calò  3 , Remo Guerrini  1   4
Affiliations

Novel Mixed NOP/Opioid Receptor Peptide Agonists

Salvatore Pacifico et al. J Med Chem. .

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.

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Conflict of interest statement

The authors declare the following competing financial interest(s): S.P., V.A., D.I., C.T., E.M., C.R., D.P., G.C., and R.G. are inventors of the patent application (102020000025972) focused on NOP/mu mixed agonists. G.C. and R.G. are founders of the University of Ferrara spin off company UFPeptides s.r.l., the assignee of such patent application. C.R. is CEO of UFPeptides s.r.l.

Figures

Figure 1
Figure 1
SAR investigation leading to a series of [Tyr/Dmt1,Xaa5]N/OFQ(1-13)-NH2 peptide derivatives as possible mixed NOP/opioid receptor ligands.
Figure 2
Figure 2
Effects of [Dmt1,5]N/OFQ(1-13)-NH2 at NOP and classical opioid receptors in calcium mobilization studies.
Figure 3
Figure 3
(A) Orthosteric site of [Dmt1,5]N/OFQ(1-9)-NH2 (colored purple) in the active mu receptor, according to “in silico” docking and MD (starting receptor structure from PDB code 6DDF). Only the first five residues are shown. The reported DAMGO conformation (the same PDB code) is superimposed (yellow). (B) Hydrophobic contacts between Dmt1, Phe4, and Dmt5 with their neighboring residues. (C–E) Interaction histograms of residues Dmt1, Phe4, and Dmt5, respectively, including hydrophobic, polar, H-bonds, water bridges of first and second order, salt bridges, and π–cation and π–π stacking as derived from long-lasting MD.
Figure 4
Figure 4
Maps of hydrophobic (A), polar (B), H-bond (C), π–π stacking (D), and π–cation (E) interactions between the mu receptor and the studied ligands along MD trajectories. Only residues 1–5 are considered for [Dmt1,5]N/OFQ(1-9)-NH2 and N/OFQ(1-9)-NH2.
Figure 5
Figure 5
Effect of [Dmt1,5]N/OFQ(1-13)-NH2 on citric acid-induced cough in conscious guinea pigs. Schematic representation of the experimental procedure for the cough measurement in conscious guinea pigs and pooled data of cough number after [Dmt1,5]N/OFQ(1-13)-NH2 (1 mM) or vehicle (0.9% NaCl) nebulization, 30 min before the nebulization of the tussive agent, citric acid (0.4 M). Values are the mean ± SEM of the numbers of coughs/15 min, with data points overlaid (n = 6 guinea pigs for each condition). *p < 0.05 vs vehicle, Student’s t-test.
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