# Investigating the Landscape of C6-Azaindole Side Chain on the Epoxymorphinan Skeleton via the Nitrogen Walk Concept: A Strategy to Enhance Drug-Like Properties

## TL;DR

Researchers designed new opioid receptor blockers by modifying a drug's side chain, aiming to treat opioid use disorder more effectively with fewer side effects.

## Contribution

A novel 'nitrogen-walk' strategy was applied to optimize MOR antagonists by systematically replacing CH groups with nitrogen atoms on the indole ring.

## Key findings

- 36 analogues were synthesized and eight showed MOR antagonist activity.
- Compound 7 was the most potent in antinociception tests and caused fewer withdrawal symptoms than naloxone.
- Modifications to the indole ring improved drug-like properties and selectivity.

## Abstract

Opioid use disorder (OUD) affects 2.1 million people
in the U.S.,
and current treatments have significant limitations. Therefore, there
is a critical need for novel, selective, potent, and reversible mu
opioid receptor (MOR) antagonists for OUD treatment. The “message-address”
concept applied to the naltrexone skeleton keeps the epoxymorphinan
core (message) consistent while modifying the C-6 substituent (address).
This approach led to the development of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(indole-7-carboxamido)­morphinan
(NAN). In this study, we have designed and evaluated NAN analogues to enhance their pharmacological properties
by applying the “nitrogen-walk” concept, i.e., replacing
each CH group with a nitrogen atom on the indole ring sequentially
while exploring different attachment positions onto the azaindole
ring. A total of 36 analogues were synthesized and characterized.
Competitive binding assays and functional activity studies identified
eight potential MOR antagonists, with compound 7 showing
the highest potency in a mouse antinociception model and inducing
fewer withdrawal symptoms than naloxone.