Researchers have uncovered the binding mechanism of an important pain receptor.
The researchers have revealed the activation of the opioid receptor, which can be found in the central nervous system, gastrointestinal tract and other peripheral tissues.
The results, uncovered by researchers from the University of Bonn, will facilitate the development of new active substances.
The opioids used today to treat severe pain can be addictive and sometimes have life-threatening side effects – with both America and Canada declaring a national health crisis in the face of opioid addiction.
The results are published in the renowned journal Science Advances.
Opioid painkillers
Opioids include, for instance, morphine or oxycodone, which has been prescribed very carelessly in the USA. This has resulted in serious consequences: hundreds of thousands of patients have become addicted after using opioids for long-term pain; many who partake in illicit opioid use.
Many of these patients later ended up on drugs such as heroin or fentanyl.
Oxycodone binds to so-called opioid receptors in the body. There are three different types: MOP, DOP and KOP. The painkillers available to date mainly activate the MOP (also called μ-opioid receptor).
However, stimulating MOP can not only be addictive, it can also have life-threatening side effects. The most serious is respiratory paralysis, which is why the most common cause of death after heroin use is respiratory arrest.
Professor Dr Christa Müller from the Pharmaceutical Institute at the University of Bonn, said: “Drugs that selectively bind to the DOP receptor probably do not have these dramatic side effects.”
The emphasis is on ‘selective’: the opioid receptors are so similar that many drugs activate all three forms. In order to find substances that only dock to the DOP receptor, it is therefore necessary to know exactly what happens during the binding process.
Spatial structure at the atomic level
Masters student, Tobias Claff, who carried out the majority of the experiments, said: “We have activated the DOP receptor with two different molecules, purified the complex and then elucidated its structure using X-rays.”
For this purpose, the complex of receptor and active substance is transformed into a crystalline state. The crystal lattice deflects the X-ray light in a characteristic manner. The intensity distribution of the diffracted radiation can therefore be used to deduce the spatial structure of the complex, right down to the arrangement of each individual atom.
“This enabled us to show which parts of the receptor are responsible for binding the drugs,” says Claff. “This knowledge should now enable the development of targeted new substances that only activate DOP.”
There is great interest in such drugs, not least because, unlike its MOP counterpart, the DOP receptor is not primarily effective against acute pain, but against chronic pain. This is currently very difficult to treat.
X-ray crystallography is not a new technique. However, the structure of G protein-coupled-receptors (including opioid receptors) could not be resolved until recently. These membrane proteins are located in the thin, fat-like membrane that surrounds the cell contents like a kind of bag. Their fat solubility means that they have to be stabilised at great effort during crystallisation. Otherwise they denature and change their spatial structure as a result.
Müller said: “There are only a few laboratories in the world that are capable of dealing with these problems.”
Professor Müller emphasised that it is not often a master’s student tackles such a complex problem. “This success is an extraordinary achievement,” she says.
