Drugs that target opioid receptors sometimes have severe side effects. Thousands of people around the world die every day from overdoses involving opioids such as fentanyl. An international team of researchers has taken a closer look at the molecular mechanisms of these active substances. The research has now been published in the journal Nature.

Opioid receptors are of great pharmacological interest because opioid substances regulate the perception of pain. “Our findings provide insights into how an opioid receptor can perform different functions. It is able to reduce pain, but also to regulate digestion or breathing,” explains a co-first author of the study.

In the current study, a  collaborative research group with discovered that superagonists, such as fentanyl, stabilise a state of the receptor that causes particularly effective and long-lasting signal transmission. This means that superagonists are particularly potent and therefore dangerous. In the current study, the researchers used electron spin resonance and single-molecule fluorescence spectroscopy to determine different states of the opioid receptor and the structural effects of different binding partners.

Opioid receptors are members of the large family of G protein-coupled receptors (GPCRs), which control many signalling processes in the body, such as taste and smell, while others bind neurotransmitters and hormones or are activated by light. Understanding the molecular interactions of these receptors with drugs and other signalling proteins is very important for drug development. As all GPCRs are structurally very similar, the researchers hope that their findings on the opioid receptor can be applied to other receptors.

The researchers identify several conformations of the cytoplasmic face of the receptor that interconvert on different timescales, including a pre-activated conformation that is capable of G-protein binding, and a fully activated conformation that markedly reduces GDP affinity within the ternary complex.

Interaction of β-arrestin-1 with the μOR core binding site appears less specific and occurs with much lower affinity than binding of G_i.

“This study involved isolating the opioid receptors. They are normally found in the body’s cells, interacting with many other proteins and molecules. Further research into the molecular interactions is therefore needed to gain a full understanding of the regulatory mechanisms,” says the author. The new study is an important building block in basic research, with further studies needed to ultimately develop better and safer medicines.

https://www.nature.com/articles/s41586-024-07295-2

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fligand-efficacy&filter=22