Dihydrokavain

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Dihydrokavain
Chemical structure of dihydrokavain Dihydrokavain.svg
Chemical structure of dihydrokavain
An accurate three dimensional representation of the molecule of Dihydrokavain in ball-and-stick format Dihydrokavain 3D BS.png
An accurate three dimensional representation of the molecule of Dihydrokavain in ball-and-stick format
Names
IUPAC name
4-Methoxy-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-2-one
Other names
Dihydrokawain
Marindinin
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
UNII
  • InChI=1S/C14H16O3/c1-16-13-9-12(17-14(15)10-13)8-7-11-5-3-2-4-6-11/h2-6,10,12H,7-9H2,1H3 X mark.svgN
    Key: VOOYTQRREPYRIW-UHFFFAOYSA-N X mark.svgN
  • InChI=1/C14H16O3/c1-16-13-9-12(17-14(15)10-13)8-7-11-5-3-2-4-6-11/h2-6,10,12H,7-9H2,1H3
    Key: VOOYTQRREPYRIW-UHFFFAOYAX
  • COC1=CC(=O)OC(C1)CCC2=CC=CC=C2
Properties
C14H16O3
Molar mass 232.27 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Dihydrokavain is one of the six major kavalactones found in the kava plant. [1] It showed the highest systemic exposure among all six major kavalactones tested, indicating it may play a central role in kava's pharmacological effects in humans. The anxiolytic effects of kava are primarily attributed to dihydrokavain.

In animal models, such as socially isolated chicks, dihydrokavain reduces anxiety-related distress without causing the sedation typically seen with standard anxiolytic drugs. Beyond its anxiolytic properties, dihydrokavain has demonstrated anti-inflammatory and analgesic effects, including inhibition of cyclooxygenase (COX) enzymes and suppression of tumor necrosis factor alpha (TNFα). It also shows potential anti-diabetic activity by activating AMP-activated protein kinase (AMPK) signaling and improving glycemic control in Drosophila models. Additionally, dihydrokavain inhibits several cytochrome P450 enzymes, indicating a potential for drug interactions, and shares structural similarities with strobilurins, contributing to mild fungicidal activity.

Pharmacology

Kava extract reduces anxiety-related distress in chicks mainly due to its dihydrokavain content, which provides anxiolytic effects without the sedation caused by standard drugs like chlordiazepoxide. [2] Dihydrokavain showed the highest systemic exposure among all six major kavalactones tested, indicating it may play a central role in kava's pharmacological effects in humans. [3] Additionally, intraperitoneal administration of dihydrokavain (150 mg/kg) in mice produced a significant analgesic effect. [4]

Among the six major kavalactones, it showed the strongest inhibition of norepinephrine-induced calcium signaling in lung cancer cells by antagonizing β-adrenergic receptors, suggesting its potential role in kava's anxiolytic and cancer-preventive effects. [5]

Dihydrokavain has been shown to inhibit cyclooxygenase enzymes, reducing COX-1 activity by approximately 58% and COX-2 by 28%, suggesting potential anti-inflammatory effects. [6] It also reduces TNFα secretion in lipopolysaccharide-stimulated THP-1 cells (a human acute monocytic leukemia-derived cell line) at a concentration of 50 μg/mL. [7]

In vitro studies show that dihydrokavain inhibits the cytochrome P450 enzymes CYP2C9 (IC50 = 130.95 μM), CYP2C19 (IC50 = 10.05 μM), and CYP3A4 (IC50 = 78.59 μM), indicating potential drug interaction risks. [8]

Dihydrokavain bears some structural similarity to the strobilurins and has some fungicidal activity. [9]

An analogue of the molecule, 56DHK, is a compound in Alpinia mutica and improves hyperglycemia in a diabetic Drosophila model by activating AMP-activated protein kinase (AMPK) signaling and modulating related metabolic genes, showing potential as a novel anti-diabetic agent. [10]

References

  1. ↑ Malani, Joji (2002-12-03). "Evaluation of the effects of Kava on the Liver" (PDF). Fiji School of Medicine. Archived from the original (PDF) on 2009-03-20. Retrieved 2009-09-04.
  2. ↑ Feltenstein, MW; LC Lambdin; M Ganzera; H Ranjith; W Dharmaratne; NP Nanayakkara; IA Khan; KJ Sufka (March 2003). "Anxiolytic properties of Piper methysticum extract samples and fractions in the chick social-separation-stress procedure". Phytotherapy Research. 17 (3): 210–216. doi:10.1002/ptr.1107. PMID   12672148. S2CID   10548965.
  3. ↑ Kanumuri, Siva Rama Raju; Mamallapalli, Jessica; Nelson, Robyn; McCurdy, Christopher R.; Mathews, Carol A.; Xing, Chengguo; Sharma, Abhisheak (28 October 2022). "Clinical pharmacokinetics of kavalactones after oral dosing of standardized kava extract in healthy volunteers". Journal of Ethnopharmacology. 297 115514. doi:10.1016/j.jep.2022.115514. PMC   9634089 . PMID   35777607.
  4. ↑ Norgren, L. (1990). "Non-surgical treatment of critical limb ischaemia". European Journal of Vascular Surgery. 4 (5): 449–454. doi:10.1016/s0950-821x(05)80781-9. PMID   2226874.
  5. ↑ Botello, Jordy F.; Corral, Pedro; Bian, Tengfei; Xing, Chengguo (2020). "Kava and its Kavalactones Inhibit Norepinephrine-induced Intracellular Calcium Influx in Lung Cancer Cells". Planta Medica. 86 (1): 26–31. Bibcode:2020PlMed..86...26B. doi:10.1055/a-1035-5183. PMID   31711251. (Erratum:  doi:10.1055/a-1158-2228, PMID   31711251 . If the erratum has been checked and does not affect the cited material, please replace {{ erratum |...}} with {{ erratum |...|checked=yes}}.)
  6. ↑ Zhao, C.; Liu, Y.; Fan, T.; Zhou, D.; Yang, Y.; Jin, Y.; Zhang, Z.; Huang, Y. (2012). "A novel strategy for encapsulating poorly soluble drug into nanostructured lipid carriers for intravenous administration". Pharmaceutical Development and Technology. 17 (4): 443–456. doi:10.3109/10837450.2010.546411. PMID   21222507.
  7. ↑ Johann, A.; Ehlert, U. (2020). "The study protocol: Neuroendocrinology and (Epi-) genetics of female reproductive transition phase mood disorder - an observational, longitudinal study from pregnancy to postpartum". BMC Pregnancy and Childbirth. 20 (1): 609. doi: 10.1186/s12884-020-03280-5 . PMC   7545379 . PMID   33036563.
  8. ↑ Zedda, M.; Lepore, G.; Gadau, S.; Manca, P.; Farina, V. (2004). "Morphological and functional changes induced by the amino acid analogue 3-nitrotyrosine in mouse neuroblastoma and rat glioma cell lines". Neuroscience Letters. 363 (2): 190–193. doi:10.1016/j.neulet.2004.04.008. PMID   15172113.
  9. ↑ Zakharychev, Vladimir V; Kovalenko, Leonid V (1998-06-30). "Natural compounds of the strobilurin series and their synthetic analogues as cell respiration inhibitors". Russian Chemical Reviews . 67 (6): 535–544. Bibcode:1998RuCRv..67..535Z. doi:10.1070/rc1998v067n06abeh000426. ISSN   0036-021X. S2CID   95676421.
  10. ↑ Hadiza Muhammad Maiturare; Mudassir Aliyu Magaji; Muhammad Kabiru Dallatu; Kabir Magaji Hamid; Mustapha Umar Imam; Ibrahim Malami (2022). "5,6-dehydrokawain improves glycaemic control by modulating AMPK target genes in Drosophila with a high-sucrose diet-induced hyperglycaemia". Phytomedicine Plus. 2 (2): 100261–. doi: 10.1016/j.phyplu.2022.100261 . ISSN   2667-0313. S2CID   247649601.


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