Finding Out Anesthetics’ Mode Of Action

When I think about how drug discovery has changed in the last 100 years, one of the first things that comes to mind is how much more target-focused the process is. Take aspirin as an example of the earlier model. Researchers didn't confirm how aspirin worked until John Vane's landmark 1971 paper, over 70 years since aspirin first hit the market. Compare that to today's world of drugmaking, where oftentimes researchers have to validate a target- show that it is connected to a disease and that modifying its activity might help treat that disease- before drug discovery can really get going. We've written about this process many times- see this account of the development of Lexicon drug candidate LX1031 for irritable bowel syndrome as an example. But there's at least one class of drugs where this target-based philosophy is in its infancy- anesthetic drugs. That's because researchers are only beginning to understand the molecular basis of anesthesia. So it's not clear which proteins to target or even whether you'd want a molecule that's selective for one target. The New York Times spoke with Harvard anesthesiologist Emery Brown last month about the neurobiology of anesthesia, and how being under actually is more like a coma than going to sleep. Other researchers are trying to understand anesthesia at the molecular level, like chemists Ivan Dmochowski and Bill Dailey, and anesthesiologist Rod Eckenhoff of the University of Pennsylvania. I visited their labs yesterday on a jaunt to Philadelphia. They're among a small number of research teams building fluorescent or light-reactive versions of the anesthetics used in hospitals every day*, in order to figure out what proteins they interact with and which of those are relevant to inducing anesthesia. They've got their work cut out for them- for one thing, the anesthetics that are administered by inhalation, such as isoflurane and sevoflurane, bind to a slew of proteins. But if their efforts pay off, they say they will eventually be able to help chemists build better, safer anesthetics.

After exposure to light, azi-isoflurane reacts with proteins.ACS Chemical Neuroscience

More reading: Molecular targets underlying general anesthesia, NP Franks, Br. J. Pharmacol. 2006, 147, S72. *by anesthesiologists like the guy I married, in the interest of full disclosure.

Author: Carmen Drahl

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