Synthesis and Pharmacological Characterization of Nociceptin/Orphanin FQ Dimeric Ligands
The neuropeptide nociceptin/orphanin FQ (N/OFQ) plays a key role in regulating several physiological functions and pathological states, which makes its receptor (NOP) a promising target for therapeutic interventions. In this study, we synthesized homodimeric N/OFQ-NH<sub>2</sub> derivatives linked by disulfide bonds between cysteines appropriately introduced in the addressing region of the native peptide in place of the original amino acids. The <i>in vitro</i> activity of the compounds was evaluated using both an NOP-G protein interaction BRET assay and a calcium mobilization assay. The most potent compound, <b>1h</b> (pEC<sub>50</sub> > 9), was obtained by coupling two monomeric precursors via a Leu<sup>14</sup>-to-Cys substitution. <i>In vivo</i>, <b>1h</b> demonstrated 3-fold greater potency than N/OFQ in eliciting loss of the righting reflex in mice and produced a long-lasting effect monitored for up to 7 h, supporting multimerization as a viable approach to developing long-acting peptide-based NOP ligands.
Authors
- Salvatore Pacifico (ORCID: https://orcid.org/0000-0002-3377-5107)
- Davide Illuminati (ORCID: https://orcid.org/0000-0002-0321-1941)
- Erika Marzola (ORCID: https://orcid.org/0000-0002-1428-1363)
- Chiara Sturaro (ORCID: https://orcid.org/0000-0002-2708-9223)
- Girolamo Calò (ORCID: https://orcid.org/0000-0001-5436-959X)
- Chiara Ruzza (ORCID: https://orcid.org/0000-0003-1360-202X)
- Delia Preti (ORCID: https://orcid.org/0000-0002-1075-3781)
- Valentina Albanese (ORCID: https://orcid.org/0000-0002-1947-2644)
- Michela Argentieri
- Erika Morrone
- Giulio Meneguzzo (ORCID: https://orcid.org/0009-0007-7049-7576)
- Remo Guerrini (ORCID: https://orcid.org/0000-0002-7619-0918)
- Davide Malfacini (ORCID: https://orcid.org/0000-0003-4562-9550)
- Tiziano De Ventura (ORCID: https://orcid.org/0000-0003-0534-9087)
- Angela Maria Rizzo (ORCID: https://orcid.org/0000-0002-8582-0432)
- P. Pola
- Alessia Frezza
Institutions
- University of Padua (IT)
- University of Ferrara (IT)
- Center for Translational Neurophysiology of Speech and Communication (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-11-04
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02350
- Primary Topic
- Neuropeptides and Animal Physiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00