Abstract
Background: The purpose of this study was to characterize the novel sedative/hypnotic agent HSK3486, a 2,6-disubstituted alkylphenol analogue. Methods: The mechanism of action of HSK3486 was studied in competitive binding assays and whole-cell patch clamp assays. HSK3486 was administered by bolus intravenous injection to dogs and rats, and the loss of righting reflex as well as effects on the cardiovascular and respiratory systems were assessed. The in vitro metabolism of HSK3486 was analyzed by CYP450 genotyping and enzyme inhibition. Results: HSK3486 competed with t-butylbicycloorthobenzoate (TBOB) and t-butylbicyclophosphorothionate (TBPS) for binding to the gamma-aminobutyric acid type A (GABAA) receptor. HSK3486 potentiated GABA-evoked chloride currents at lower concentrations while activating GABAA receptor at higher concentrations. HSK3486 induced hypnosis in rats and dogs, and had a higher therapeutic index than propofol in rats. The hypnotic potency of HSK3486 was approximately 4-5 fold higher than that of propofol. HSK3486 exerted minimal effects on the cardiovascular system. Conclusions: HSK3486 is a positive allosteric regulator and direct agonist of GABAA receptor. It has a promising sedative/hypnotic effect and good in vivo pharmacokinetic properties, which justify further studies towards its clinical application.
Highlights
Propofol is the most widely used sedative/hypnotic agent for the induction and maintenance of general anesthesia and sedation of patients in intensive care units (ICUs) (Grasshoff and Antkowiak, 2004; Cravero et al, 2009)
The 2,6-disubstituted alkylphenol HSK3486 is a novel propofol analogue formulated in an injectable emulsion of medium- and long-chain triglycerides similar to that used for propofol (James and Glen, 1980)
The anesthetic effects of HSK3486 were evaluated in SpragueDawley rats and the hemodynamic effects of HSK3486 were evaluated in beagle dogs purchased from Charles River (Beijing, China), Covance Research Products (New Jersey, United States) or Beijing Marshall Biotechnology (Beijing, China)
Summary
Propofol is the most widely used sedative/hypnotic agent for the induction and maintenance of general anesthesia and sedation of patients in intensive care units (ICUs) (Grasshoff and Antkowiak, 2004; Cravero et al, 2009). Injection pain may depend on the propofol concentration in the injectable emulsion, and HSK3486, a Novel General Anesthetic infusion syndrome may be caused by a high concentration of lipids in the emulsion (Desousa, 2016). For the same level of anesthesia, fewer lipids from the HSK3486 emulsion reach the circulatory system than in the case of a propofol emulsion (Qin et al, 2017). The purpose of this study was to characterize the novel sedative/hypnotic agent HSK3486, a 2,6-disubstituted alkylphenol analogue
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