Thousands of people worldwide die every day from overdoses of opioids such as fentanyl. Drugs that act on the opioid receptor sometimes have severe side effects. An international research team has taken a closer look at the molecular mechanisms of these drugs. The results, with the participation of Dr. Matthias Elgeti, biophysicist at Leipzig University, in cooperation with research groups from the USA and China, have been published in the renowned scientific journal Nature.
Opioid receptors are of great pharmacological interest because opioid drugs regulate the perception of pain. “Our results provide insights into how an opioid receptor can perform different functions. It is able to reduce pain, but also to regulate digestion or respiration,” explains Dr. Elgeti, co-first author of the study from the Institute for Drug Development at the Faculty of Medicine.
In the current study, the biophysicist collaborated with international scientists, including the research group of Nobel Prize winner Brian Kobilka from Stanford University. They discovered that so-called super-agonists such as fentanyl stabilize a state of the receptor that causes particularly effective and long-lasting signal transmission. This makes super-agonists particularly potent and therefore dangerous.
Opioid receptors are members of the large family of “G protein-coupled receptors” (GPCRs) that control many signaling processes in the body, for example taste and smell, while others bind neurotransmitters, hormones or are activated by light. Understanding the molecular interactions of these receptors with drugs and other signaling proteins is very important for drug development. As all GPCRs have great structural similarities, the researchers hope to be able to transfer the findings on the opioid receptor to other receptors.
“The opioid receptors were isolated for the current study. They are normally found in the cells of the body in interaction with many other proteins and molecules. Research into further molecular interactions is therefore important in order to gain a full understanding of the regulatory mechanisms,” explains Dr. Elgeti. The new study represents an important building block in basic research; further studies are necessary to ultimately develop better and safer drugs.
Original publication in Nature: Ligand efficacy modulates conformational dynamics of the µ-opioid receptor. DOI: 10.1038/s41586-024-07295-2