2025/11/04 by Valentina Albanese, Pietro Pola, P. Pola +15
Neuroscience · Immunology and Microbiology · Medicine · #Neuropeptides and Animal Physiology #Antimicrobial Peptides and Activities #Pain Mechanisms and Treatments
paper · pdf · doi:10.1021/acs.jmedchem.5c02350
High Resolution Image Download MS PowerPoint Slide 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 2 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 in vitro activity of the compounds was evaluated using both an NOP-G protein interaction BRET assay and a calcium mobilization assay. The most potent compound, 1h (pEC 50 > 9), was obtained by coupling two monomeric precursors via a Leu 14 -to-Cys substitution. In vivo, 1h 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.