Nitrogenated honokiol derivatives allosterically modulate GABAA receptors and act as strong partial agonists

Bernaskova, Marketa; Schoeffmann, Angela; Schuehly, Wolfgang; Hüfner, Antje; Baburin, Igor; Hering, Steffen

doi:10.1016/j.bmc.2015.08.034

Cited by 12 publications

(6 citation statements)

References 22 publications

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“…Benzodiazepines act as positive allosteric modulators of GABA A receptor, enhancing chloride influx leading to hyperpolarization, for binding to specific pocket on the receptor. Based on this observations, and the evidence that diverse natural products as valerenic acid (Benke et al, 2009) and honokiol (Bernaskova et al, 2015) have shown GABAergic activities, we conducted EPM in the presence of flumazenil, a benzodiazepine antagonist. The partial reversion observed in the open arm-behavior of the ALK-treated mice suggested that the GABA A receptor can mediate, at least in part, these effects.…”

Section: Discussionmentioning

confidence: 99%

High Resolution UHPLC-MS Metabolomics and Sedative-Anxiolytic Effects of Latua pubiflora: A Mystic Plant used by Mapuche Amerindians

et al. 2017

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Latua pubiflora (Griseb) Phil. Is a native shrub of the Solanaceae family that grows freely in southern Chile and is employed among Mapuche aboriginals to induce sedative effects and hallucinations in religious or medicine rituals since prehispanic times. In this work, the pentobarbital-induced sleeping test and the elevated plus maze test were employed to test the behavioral effects of extracts of this plant in mice. The psychopharmacological evaluation of L. pubiflora extracts in mice determined that both alkaloid-enriched as well as the non-alkaloid extracts produced an increase of sleeping time and alteration of motor activity in mice at 150 mg/Kg. The alkaloid extract exhibited anxiolytic effects in the elevated plus maze test, which was counteracted by flumazenil. In addition, the alkaloid extract from L. pubiflora decreased [3H]-flunitrazepam binding on rat cortical membranes. In this study we have identified 18 tropane alkaloids (peaks 1–4, 8–13, 15–18, 21, 23, 24, and 28), 8 phenolic acids and related compounds (peaks 5–7, 14, 19, 20, 22, and 29) and 7 flavonoids (peaks 25–27 and 30–33) in extracts of L. pubiflora by UHPLC-PDA-MS which are responsible for the biological activity. This study assessed for the first time the sedative-anxiolytic effects of L. pubiflora in rats besides the high resolution metabolomics analysis including the finding of pharmacologically important tropane alkaloids and glycosylated flavonoids.

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Section: Discussionmentioning

confidence: 99%

High Resolution UHPLC-MS Metabolomics and Sedative-Anxiolytic Effects of Latua pubiflora: A Mystic Plant used by Mapuche Amerindians

et al. 2017

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“…Synthesis Procedure for Compound L4. 26 Nitric acid (4 mmol, 0.18 mL) was added to a solution of magnolol (266 mg, 1 mmol) in ethyl acetate (8 mL) under stirring at room temperature. The reaction mixture was stirred for 10 min and quenched with NaOH (2 N).…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Design, Synthesis, and Structure–Activity Relationship Studies of Magnolol Derivatives as Antifungal Agents

et al. 2021

J. Agric. Food Chem.

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Plant pathogenic fungi seriously affect agricultural production and are difficult to control. The discovery of new leads based on natural products is an important way to innovate fungicides. In this study, 30 natural-product-based magnolol derivatives were synthesized and characterized on the basis of NMR and mass spectroscopy. Bioactivity tests on phytopathogenic fungi (Rhizoctonia solani, Fusarium graminearum, Botrytis cinerea, and Sclerotinia sclerotiorum) in vitro of these compounds were performed systematically. The results showed that 11 compounds were active against four kinds of phytopathogenic fungi with EC50 values in the range of 1.40–20.00 μg/mL, especially compound L5 that exhibited excellent antifungal properties against B. cinerea with an EC50 value of 2.86 μg/mL, approximately 2.8-fold more potent than magnolol (EC50 = 8.13 μg/mL). Moreover, compound L6 showed the highest antifungal activity against F. graminearum and Rhophitulus solani with EC50 values of 4.39 and 1.40 μg/mL, respectively, and compound L7 showed good antifungal activity against S. sclerotiorum. Then, an in vivo experiment of compound L5 against B. cinerea was further investigated in vivo using infected tomatoes (curative effect, 50/200 and 36%/100 μg/mL). The physiological and biochemical studies illustrated that the primary action mechanism of compound L5 on B. cinerea might change the mycelium morphology, increase cell membrane permeability, and destroy the function of mitochondria. Furthermore, structure–activity relationship (SAR) studies revealed that hydroxyl groups play a key role in antifungal activity. To sum up, this study provides a reference for understanding the application of magnolol-based antifungal agents in crop protection.

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“…In a 10 mL round-bottom flask, H12 (for synthesis, see Reference [ 11 ]) (37 mg, 0.125 mmol) was suspended with water (1 mL), and acetic anhydride (0.21 mmol, 20 μL) was added. The flask was allowed to rotate for 10 min at 80 °C in a water bath.…”

Section: Methodsmentioning

confidence: 99%

“…Biphenyls are considered privileged structures due to their over-proportionally frequent biological activity [ 8 ]. In our previous investigations, we focused on the diverse biological activities of H , M , and derivatives thereof, such as COX-1/2, 5-LOX and LTB 4 -formation [ 9 ], GABA A receptor activity [ 10 , 11 ], CB 2 receptor activity [ 12 ], and toxicity on several cancer cell lines [ 13 ]. In this paper, we focus on the activity of the compounds at the NET.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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 γ-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.

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Nitrogenated honokiol derivatives allosterically modulate GABAA receptors and act as strong partial agonists

Cited by 12 publications

References 22 publications

High Resolution UHPLC-MS Metabolomics and Sedative-Anxiolytic Effects of Latua pubiflora: A Mystic Plant used by Mapuche Amerindians

High Resolution UHPLC-MS Metabolomics and Sedative-Anxiolytic Effects of Latua pubiflora: A Mystic Plant used by Mapuche Amerindians

Design, Synthesis, and Structure–Activity Relationship Studies of Magnolol Derivatives as Antifungal Agents

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

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