How propofol works

Researchers at Washington University School of Medicine in St Louis and Imperial College London have identified the site where propofol binds to receptors in the brain to sedate patients during surgery.

The researchers believe the findings, reported in the journal Nature Chemical Biology, will eventually lead to the development of more effective anaesthetics with fewer side effects.

Alex Evers, MD, professor at the Henry E. Mallinckrodt and head of the Department of Anesthesiology at Washington University said: “We knew that intravenous anaesthetics, like propofol, act on an important receptor on brain cells called the GABAA receptor, but we didn’t really know exactly where they bound to that receptor.”

Propofol is often used because it wears off quickly and is less likely to cause nausea than many other anaesthetics. But the drug does have potentially dangerous side effects such as lowering blood pressure and interfering with breathing.

“In previous work to directly identify anaesthetic binding sites, GABAA receptors had to be extracted from membranes and purified prior to performing the binding studies,” Evers said. “Our method allowed us to study propofol binding to the intact receptor in its native membrane environment.”

Evers’ laboratory then teamed up with a group at Imperial College that had been taking the same approach. Led by Nicholas Franks, PhD, professor of biophysics and anaesthetics, the group has spent years creating a photoanalogue of propofol that both behaves in precisely the same way as propofol and contains a labelling group that permanently attaches to its binding site on the GABAA receptor when exposed to a specific wavelength of light.

“For the purposes of this research, we wanted to create an analogue that behaved exactly like propofol except that we could activate this chemical hook to permanently bind the drug to the receptor. The next step was then to extract the receptor, cut it into pieces and identify the precise piece of the protein where the propofol analogue had attached to the receptor. This was the tricky step that the Evers group at Washington University had perfected.”

Evers said: “Anaesthetics have desirable effects, but they also have undesirable [ones]. By understanding precisely what the binding sites look like on the proteins that induce those potential problems, we eventually hope to design and select for drugs that have the benefits we want without dangerous side effects.”

Evers and Franks now plan to identify binding sites of other anaesthetics. They believe their approach also can be used to study other types of drugs, such as psychiatric and anti-seizure drugs.

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