Bioinspired Honokiol Analogs and Their Evaluation for Activity on the Norepinephrine Transporter

• Type of Material: Article
• Authors: Kristen Stout, Emory University; Marketa Bernaskova, University of Graz; Gary Miller, Emory University; Antje Hufner, University of Graz; Wolfgang Schuehly, University of Graz
• Language: English
• Date: 2018-10-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2018 MDPI AG. All rights reserved.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/molecules23102536
• Title of Journal or Parent Work: Molecules
• ISSN: 1420-3049
• Volume: 23
• Issue: 10
• Grant/Funding Information: Parts of this work were supported by the Austrian Science Fund (FWF) under a grant “Synthesis of new GABAA receptor modulators” (P21241).
• Keywords: ASSAY; Magnolia officinalis; honokiol derivatives; norepinephrine transporter; HEK cell expressing hNET; Life Sciences & Biomedicine; Physical Sciences; diphenylmethanes; Chemistry, Multidisciplinary; Chemistry; Biochemistry & Molecular Biology; Science & Technology; MAGNOLOL; biphenyl-type neolignans; DERIVATIVES
• Research Categories: Biology, Molecular; Chemistry, Biochemistry

Abstract

In traditional Asian medicinal systems, preparations of the root and stem bark of Magnolia species are widely used to treat anxiety and other nervous disturbances. The biphenyl-type neolignans honokiol and magnolol are the main constituents of Magnolia bark extracts. In the central nervous system, Magnolia bark preparations that contain honokiol are thought to primarily interact with -aminobutyric acid A (GABAA) receptors. However, stress responses inherently involve the noradrenergic system, which has not been investigated in the pharmacological mechanism of honokiol. We present here interactions of honokiol and other synthesized biphenyl-type neolignans and diphenylmethane analogs with the norepinephrine transporter (NET), which is responsible for the synaptic clearance of norepinephrine and the target of many anxiolytics. Of the synthesized compounds, 16 are new chemical entities, which are fully characterized. The 52 compounds tested show mild, non-potent interactions with NET (IC50 > 100 μM). It is thus likely that the observed anxiolytic effects of, e.g., Magnolia preparations, are not due to direct interaction with the noradrenergic system.