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Design, Synthesis, and Characterization of Novel, Subtype-Selective Fluorescent Antagonists Targeting the Nociceptin/Orphanin FQ Opioid Peptide Receptor

Year: 2025

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide The nociceptin/orphanin FQ opioid peptide receptor (NOPr) is a member of the opioid receptor family under investigation for the treatment of depression, Parkinson’s disease, addiction, and pain. Opioid analgesics such as morphine act through μ-opioid receptor (MOPr) activation but cause MOPr-driven side effects that include respiratory depression, tolerance, addiction, and constipation. Bivalent NOPr/MOPr agonists have been shown to confer effective analgesia with an improved side effect profile. However, the development of new NOPr-targeting drugs is challenged by a paucity of pharmacological tools to characterize NOPr-ligands and visualize receptor expression. We report the design, synthesis, and pharmacological evaluation of the first high affinity small molecule NOPr-targeting fluorescent ligands, based on the antagonist: (2 R )-1-(phenylmethyl)- N -(3-spiro[1 H -2-benzofuran-3,4′-piperidine]-1′-ylpropyl)pyrrolidine-2-carboxamide ( C24 ). These ligands display excellent selectivity for the NOPr against MOPr, δ (DOPr), and κ (KOPr) opioid receptors and are effective tracers for competition binding assays to evaluate NOPr-ligand affinity and in live cell imaging to visualize NOPr expression.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.5c02707