The drugs that render patients unconscious for surgery are effective, but they can have serious side effects. The commonly used intravenous anesthetic propofol, for example, lowers blood pressure, which is especially risky for the very young, the very old and those who have suffered trauma. (Propofol is the drug that figured into the death of singer Michael Jackson.)
A safer way to put patients to sleep is needed, but much remains unknown about how anesthetics work. Researchers do know, however, that propofol acts on gamma-aminobutyric acid (GABA) receptors, which normally respond to GABA, a small molecule that turns down the activity of neurons.
Armed with that bit of knowledge, Edward Bertaccini, MD, professor of anesthesiology, perioperative and pain medicine, and his fellow researchers set out to design a new drug. Using molecular modeling software, they asked the computer to find molecules that enhance GABA receptor function (thereby dialing down neural activity) by binding to the same molecular site as propofol.
The software works "sort of like the ball-and-stick models from high school chemistry class," Bertaccini said, except that it uses calculations that account for molecular mechanics.
The computer identified 12 compounds, and the researchers were able to obtain 11 of them commercially. The scientists tested the compounds in brain tissue to see if they activated GABA receptors; they also checked to see whether the compounds put tadpoles to sleep.
Seven of the 11 passed the tests, but one stood out as the most potent: compound BB. They tried it out, and realized they'd found a potential winner.
"It's just as good -- if not better -- at putting rats to sleep, and it's much better at keeping blood pressure up," Bertaccini said.
The work appears in the Proceedings of the National Academy of Sciences. Bertaccini said they plan further studies to ensure that compound BB is safe and effective.
He added that less risky anesthetics are desperately needed in developing countries, which lack anesthesiologists to monitor patients during surgery and in emergency situations. They could also help troops in combat situations.
"I'm looking for a drug that will help them take care of the sickest of the sick," he said.
Photo by Rachel Baker
