Illuminating Anesthetic Targets

A photoreactive analog of a common inhaled anesthetic might shed light on the targets and binding sites of these promiscuous drugs. Volatility and low binding affinities plague efforts to pin down molecular targets for inhaled anesthetics such as isoflurane and sevoflurane, which are used every day in operating rooms worldwide. One way to get around those drawbacks is to synthesize versions of anesthetics with light-reactive moieties. However, current analogs have some disadvantages: They aren’t exact mimics of known anesthetics, or they contain photoreactive groups that preferentially react with certain amino acids, potentially biasing the probes toward some binding sites and not others. Now, anesthesiologist Roderic G. Eckenhoff of the University of Pennsylvania School of Medicine and a multi-institution team have developed azi-isoflurane, a photoreactive mimic of isoflurane that has neither of those drawbacks (ACS Chem. Neurosci., DOI: 10.1021/cn900014m). Azi-isoflurane binds in known isoflurane binding pockets in two model proteins and is a more potent anesthetic than isoflurane in vivo. The team hopes to use azi-isoflurane to identify molecular targets underlying both the desirable and undesirable effects of isoflurane.