Design, Synthesis, and Evaluation of a Series of Novel Benzocyclobutene Derivatives as General Anesthetics

In the present work, a series of structurally novel benzocyclobutene derivatives were identified as general anesthetics through the loss of righting reflex (LORR) experiment on mice. Our initial efforts found compound 1a with a fused four-membered ring on the 2,3-position of the phenol ring could significantly improve the safety profile. Further SAR study revealed that small hydrogen bond acceptor (HBA) groups are optimal for good ED₅₀ along with much broader therapeutic windows, such as compounds 16b and 17. Present work demonstrates the superiority of this novel benzocyclobutene scaffold.