Phenotypic discovery of GABAA receptor-mediated general anesthetics with analgesic activity

General anesthetics are essential for invasive medical procedures; however, there remains a need for safer agents. Using a bespoke 96-well-plate format platform enabling high-throughput imaging of larval zebrafish behavior, we screened 12,000 compounds and identified an isoxazole chemotype that phenocopies the intravenous anesthetics etomidate and propofol. Its optimization via medicinal chemistry yielded a novel anesthetic that we call nidradine. This anesthetic is efficacious in both zebrafish and mice and lacks the problematic adrenal suppression characteristic of etomidate. Mechanistic studies via electrophysiology and structural biology revealed that nidradine, like etomidate and propofol, is a positive allosteric modulator of the GABA _A receptor. Remarkably, behavioral assays in mice demonstrate that nidradine differs from most general anesthetics in that it also produces analgesia.