New opioid drugs with less addictive potential could be on the way thanks to a study revealing how morphine derivatives bind to a receptor.
Opioid painkillers act on several receptors in the brain. Most of their effects are brought about through the mu opioid receptor, but this pathway is associated with severe side effects, including physical dependence and suppression of breathing, which can be fatal. Over 50,000 deaths were attributed to opioids in the US in 2016.
Another subtype, the kappa opioid receptor, can also聽reduce pain. Drugs that target it selectively don鈥檛 seem to be rewarding and addictive, but they have other severe side effects, like types of depression and hallucinations.
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Daniel Wacker at the University of North Carolina School of Medicine and colleagues used X-ray crystallography to examine the structure of the kappa receptor bound to a morphine derivative, revealing which parts of the protein are important for its activation.
His collaborators then used computer modelling to design a new molecule that binds tightly to the kappa receptor, but not other opioid receptors. Lab experiments showed that it worked as expected in cells.
With a deeper understanding of the receptor structure, the team hope it will be possible to develop safer painkillers, with fewer of the unpleasant side effects.聽鈥淚 firmly believe that these studies will really help accelerate the design of alternative compounds targeting the kappa receptor, that we know don鈥檛 have the addictive potential that mu compounds have,鈥� says Wacker.
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