Pharmacodynamics and Pharmacokinetics of HSK3486, a Novel 2,6-Disubstituted Phenol Derivative as a General Anesthetic
The purpose of this study was to characterize the novel sedative/hypnotic agent HSK3486, a 2,6-disubstituted alkylphenol analogue. 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 t...
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Published in | Frontiers in pharmacology Vol. 13; p. 830791 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
Frontiers Media S.A
03.02.2022
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Subjects | |
Online Access | Get full text |
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Summary: | The purpose of this study was to characterize the novel sedative/hypnotic agent HSK3486, a 2,6-disubstituted alkylphenol analogue.
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
metabolism of HSK3486 was analyzed by CYP450 genotyping and enzyme inhibition.
HSK3486 competed with t-butylbicycloorthobenzoate (TBOB) and t-butylbicyclophosphorothionate (TBPS) for binding to the gamma-aminobutyric acid type A (GABA
) receptor. HSK3486 potentiated GABA-evoked chloride currents at lower concentrations while activating GABA
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.
HSK3486 is a positive allosteric regulator and direct agonist of GABA
receptor. It has a promising sedative/hypnotic effect and good
pharmacokinetic properties, which justify further studies towards its clinical application. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewed by: Youssef Jounaidi, Massachusetts General Hospital and Harvard Medical School, United States These authors have contributed equally to this work Edited by: Apostolos Zarros, University of Glasgow, United Kingdom Gustav Akk, Washington University in St. Louis, United States This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology |
ISSN: | 1663-9812 1663-9812 |
DOI: | 10.3389/fphar.2022.830791 |