Antagonism of Propofol Anesthesia by Alkyl-fluorobenzene Derivatives

Abstract

Abstract Despite their frequent use across many clinical settings, general anesthetics are medications with lethal side effects and no reversal agents. A fluorinated analogue of propofol has previously been shown to antagonize propofol anesthesia in tadpoles and zebrafish, but little further investigation of this class of molecules as anesthetic antagonists has been conducted. A 13-member library of alkyl-fluorobenzene derivatives was tested in an established behavioral model of anesthesia in zebrafish at 5 days post fertilization. These compounds were examined for their ability to antagonize propofol and two volatile anesthetics, as well as their binding to the anesthetic-binding model protein apoferritin. The two compounds demonstrating highest antagonistic potency were found to bind apoferritin in a manner similar to propofol. Selected compounds did not show antagonism of volatile anesthetics, indicating some selectivity of this antagonism. Similarities in structure and binding to apoferritin as well as a Schild analysis are suggestive of competitive antagonism, but like the anesthetics, the potential mechanism(s) of these antagonists will require further mechanistic investigation.