Media release

From: Springer Nature

The development of a compound that enhances the effectiveness of naloxone, a drug used to treat opioid overdose, is reported in Nature this week. The identification of compounds that work cooperatively with naloxone could help the treatment of overdoses from potent and long-lasting opioids such as fentanyl.

The overuse of opioids for pain relief has increased the risk of addiction and abuse, fuelling an opioid overdose epidemic. Naloxone (Narcan) is a common and effective treatment for opioid overdoses and is a lifesaving tool, but repeated doses are needed to treat overdoses from highly potent and long-lasting opioids such as fentanyl. Molecules that act on opioid receptors, specifically the µ-opioid receptor, may help to prevent opioid overdose deaths, but promising candidates have remained elusive.

A potential candidate is identified in a screen of a large chemical library, performed by Brian Kobilka and colleagues. They discovered a compound, named ‘368’, that is highly selective for the µ-opioid receptor, binding in a way that enhances the affinity of naloxone and boosts its potency by more than seven-fold. The authors show that 368 works cooperatively with naloxone to block the effects of morphine and fentanyl while minimising withdrawal symptoms. Moreover, the addition of 368 means that lower doses of naloxone are needed to produce favourable effects.

The new compound binds to a different part of the µ-opiod receptor than opioids and is known as a negative allosteric modulator. The findings demonstrate that negative allosteric modulators of the µ-opioid receptor can enhance the effectiveness of naloxone. Further screening for such compounds could uncover the mechanics of their action and improve their effectiveness, the authors suggest.