Hunting for new anesthetics

Existing anesthetics in clinical use have side effects that can make the drugs dangerous for vulnerable populations, such as the very young and the very old. These side effects include drops in blood pressure and inhibition of steroid biosynthesis. Anesthesiologists know how to mitigate those side effects, but drugs without them would be safer and easier to use.

A team led by Edward J. Bertaccini of Stanford University School of Medicine and the Palo Alto VA Health Care System has identified a class of compounds that could lead to a new family of anesthetics without the side effects (Proc. Natl. Acad. Sci. U.S.A. 2019, DOI: 10.1073/pnas.1822076116).

Through a series of modeling studies, one of which involved finding compounds that could bind strongly to the γ-aminobutyric acid (GABA) type A receptor, the researchers identified N-aryl pyrroles as a class of molecules to pursue. They searched compound databases for molecules with that core and turned up 11 commercially available diphenyl N-aryl pyrroles, none of which had been considered as anesthetics. The compounds exhibited anesthetic effects in frogs and rats. The tests in rats showed that the most potent compound doesn’t cause drops in blood pressure, even at doses of about five times the amount needed to knock out the rats.

Bertaccini is collaborating with Stanford’s SPARK drug development program to do preliminary toxicology and formulation studies on the lead compound.

Stuart A. Forman, an anesthesiologist at Massachusetts General Hospital, points out that there’s a history of potential anesthetics failing to reach the market and being unable to compete with propofol, the most popular anesthetic, if they do.

“Anesthesia providers have managed to adapt their use of propofol and other available induction agents to ameliorate dangers to vulnerable patients. Until an alternative anesthetic drug with superior overall clinical performance is developed, this state of affairs will persist,” Forman says. “Only time and more scientific work will tell if the diphenyl-pyrroles can meet this challenge.”