# Synthesis and Biological Evaluation of Novel Biased Mu-Opioid Receptor Agonists

## TL;DR

This study developed new opioid drugs that reduce side effects while effectively managing pain in mice.

## Contribution

The paper introduces novel biased mu-opioid receptor agonists with improved safety profiles.

## Key findings

- Compound 6a shows analgesic effects without β-arrestin recruitment at low concentrations.
- 6a outperforms morphine in reducing respiratory depression and physical dependence.
- Molecular docking highlights the role of D147 in 6a's analgesic mechanism.

## Abstract

This study explored the potential of a series of PZM21 analogues for pain treatment. Specifically, the hydroxyphenyl ring of PZM21 was replaced with a naphthyl ring, the thienyl ring was substituted with either a phenyl ring or furan rings, and the essential dimethylamine and urea groups were retained. These compounds aimed to enhance safety and minimize the adverse effects associated with opioid drugs. The research findings suggest that compound 6a does not induce β-arrestin recruitment at low-nanomolar concentrations but exhibits significant analgesic effects in established mouse models. Compared to morphine, 6a shows advantages in alleviating respiratory depression and minimizing physical dependence. Molecular docking studies underscore the pivotal role of the D147 amino acid residue in the analgesic mechanism of 6a. Consequently, 6a is a compelling candidate for the development of safer opioid analgesics and warrants further attention.