Innovative Chemotype Could Transform Anesthetic Use

A new study describes an innovative screening process that has discovered two completely new potential anesthetics that may be safer than current drugs.

Researchers at the University of Pennsylvania (Philadelphia, USA) developed a new high-throughput screening process that employs a fluorescent surrogate for detecting on-pathway anesthetic protein targets. They then screened a 350,000 compound library, searching for compounds that compete with 1-aminoanthracene–apoferritin binding targets. Compounds that interacted strongly with apoferritin and those with the most promising structures were selected for further animal testing.

The chemotypes of 2,600 compounds with a strong presence that exhibited activity via isothermal titration calorimetry were then selected for medicinal chemistry optimization, including testing for anesthetic potency and toxicity. A subset of 700 compounds chosen by structural criteria was successfully reconfirmed in mice using the initial assay. Based on a strong presence in both the initial and secondary screens, four compounds based on 6-phenylpyridazin-3(2H) that exhibited high potency and low toxicity were tested in tadpoles, and two were found to be effective as anesthetics in mice. The study was published in the February 2015 issue of Anesthesiology.

“We are only beginning to understand the actual mechanisms that allow general anesthetics to achieve an anesthetized state, and this study is a breakthrough into that world,” said professor of anesthesiology and critical care Roderic Eckenhoff, MD. “The anesthetics identified by this approach require further development before they can be considered for use in the operating room. However, the study results show that novel anesthetics do exist, and that we need not restrict ourselves to small modifications of existing drugs.”

The screening process, which has previously been used in the development of therapeutic drugs, represents a new approach to developing anesthetics, making it possible to create new alternatives that address current safety issues. Until now, no new anesthetic classes had been developed since the 1970s.

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