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

## TL;DR

Scientists created new fluorescent drugs that target a specific opioid receptor, which could help develop better treatments for pain and addiction without harmful side effects.

## Contribution

The first high-affinity, subtype-selective fluorescent NOPr ligands were designed and characterized for pharmacological and imaging applications.

## Key findings

- The new ligands show high selectivity for NOPr over MOPr, DOPr, and KOPr receptors.
- The compounds are effective tracers for competition binding assays and live cell imaging.
- These ligands could improve drug development for pain and addiction by enabling NOPr visualization and ligand evaluation.

## Abstract

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:
(2R)-1-(phenylmethyl)-N-(3-spiro­[1H-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.