Propofol Derivative May Pave The Way For Improved Anesthetics

The intravenous drug propofol is one of the most common anesthetics used in surgery. It’s popular because it rarely causes nausea and is fast-acting, but it can cause unwanted side effects such as low blood pressure and breathing problems. Researchers seek a next-generation propofol derivative that induces unconsciousness without any side effects, but they lack exact information about how the drug works. Now, one group of scientists say they’ve uncovered propofol’s binding site at its most important protein target, an ion channel called the GABA_A receptor (Nat. Chem. Biol. 2013, DOI: 10.1038/nchembio.1340). Prior studies pointed to a propofol-binding site between subunits of the ion channel, but much of the evidence was indirect. Nicholas P. Franks of Imperial College London, Alex S. Evers of Washington University School of Medicine, in St. Louis, and colleagues report that the site is instead at the interface between the membrane-spanning part of the channel and its extracellular domain. They detected this site by developing a light-activated labeling reagent, o-propofol diazirine, with similar biological activity as propofol. They allowed the label to attach to the channel and then determined attachment points with mass spectrometry. The team plans to test whether mutations to the proposed binding site affect propofol activity in animals.