{{chembox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 450846926 | Name = Dihydrokavain | ImageFile = Dihydrokavain.svg | ImageClass = skin-invert-image | ImageSize = 180 | ImageName = Chemical structure of dihydrokavain | ImageAlt = Chemical structure of dihydrokavain | ImageFile2 = Dihydrokavain 3D BS.png | ImageClass2 = bg-transparent | ImageSize2 = 180 | ImageName2 = An accurate three dimensional representation of the molecule of Dihydrokavain in ball-and-stick format | ImageAlt2 = An accurate three dimensional representation of the molecule of Dihydrokavain in ball-and-stick forma | IUPACName = 4-Methoxy-6-(2-phenylethyl)-5,6-dihydro-2''H''-pyran-2-one | OtherNames = Dihydrokawain<br>Marindinin |Section1={{Chembox Identifiers | CASNo_Ref = {{cascite|correct|CAS}} | CASNo = 587-63-3 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = NW8ZGW9XRZ | PubChem = 98356 | SMILES = COC1=CC(=O)OC(C1)CCC2=CC=CC=C2 | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChemSpiderID = 88817 | 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 | InChIKey = VOOYTQRREPYRIW-UHFFFAOYAX | StdInChI_Ref = {{stdinchicite|changed|chemspider}} | StdInChI = 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 | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} | StdInChIKey = VOOYTQRREPYRIW-UHFFFAOYSA-N | MeSHName = }} |Section2={{Chembox Properties | Formula = C<sub>14</sub>H<sub>16</sub>O<sub>3</sub> | MolarMass = 232.27 g/mol | Appearance = | Density = | MeltingPt = | BoilingPt = | Solubility = }} }}
'''Dihydrokavain''' is one of the six major kavalactones found in the kava plant.<ref name='Malani'>{{cite journal|title=Evaluation of the effects of Kava on the Liver|journal=Fiji School of Medicine|date=2002-12-03|first=Joji|last=Malani|url=http://www.spc.int/cis/documents/Kava%20article%20DrMalani.pdf|accessdate=2009-09-04|archive-url=https://web.archive.org/web/20090320001735/http://www.spc.int/cis/documents/Kava%20article%20DrMalani.pdf|archive-date=2009-03-20|url-status=dead}}</ref> 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.<!--Per WP:CITELEAD, references are not needed in the lead if it is sourced in the body of the article.-->
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.<!--Per WP:CITELEAD, references are not needed in the lead if it is sourced in the body of the article.-->
==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.<ref>{{cite journal|last=Feltenstein|first=MW|author2=LC Lambdin |author3=M Ganzera |author4=H Ranjith |author5=W Dharmaratne |author6=NP Nanayakkara |author7=IA Khan |author8=KJ Sufka |title=Anxiolytic properties of Piper methysticum extract samples and fractions in the chick social-separation-stress procedure.|journal=Phytotherapy Research|date=March 2003|volume=17|issue=3|pages=210–216|doi=10.1002/ptr.1107|pmid=12672148|s2cid=10548965}}</ref> 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.<ref>{{cite journal |last1=Kanumuri |first1=Siva Rama Raju |last2=Mamallapalli |first2=Jessica |last3=Nelson |first3=Robyn |last4=McCurdy |first4=Christopher R. |last5=Mathews |first5=Carol A. |last6=Xing |first6=Chengguo |last7=Sharma |first7=Abhisheak |title=Clinical pharmacokinetics of kavalactones after oral dosing of standardized kava extract in healthy volunteers |journal=Journal of Ethnopharmacology |volume=297 |date=28 October 2022 |article-number=115514 |doi=10.1016/j.jep.2022.115514|pmid=35777607 |pmc=9634089 }}</ref> Additionally, intraperitoneal administration of dihydrokavain (150 mg/kg) in mice produced a significant analgesic effect.<ref>{{Cite journal |pmid=2226874 |date=1990 |last1=Norgren |first1=L. |title=Non-surgical treatment of critical limb ischaemia |journal=European Journal of Vascular Surgery |volume=4 |issue=5 |pages=449–454 |doi=10.1016/s0950-821x(05)80781-9 }}</ref>
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.<ref>{{Cite journal |doi=10.1055/a-1035-5183 |title=Kava and its Kavalactones Inhibit Norepinephrine-induced Intracellular Calcium Influx in Lung Cancer Cells |date=2020 |last1=Botello |first1=Jordy F. |last2=Corral |first2=Pedro |last3=Bian |first3=Tengfei |last4=Xing |first4=Chengguo |journal=Planta Medica |volume=86 |issue=1 |pages=26–31 |pmid=31711251 |bibcode=2020PlMed..86...26B }}{{Erratum|doi=10.1055/a-1158-2228|pmid=31711251|checked=yes}}</ref>
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.<ref>{{Cite journal |pmid=21222507 |date=2012 |last1=Zhao |first1=C. |last2=Liu |first2=Y. |last3=Fan |first3=T. |last4=Zhou |first4=D. |last5=Yang |first5=Y. |last6=Jin |first6=Y. |last7=Zhang |first7=Z. |last8=Huang |first8=Y. |title=A novel strategy for encapsulating poorly soluble drug into nanostructured lipid carriers for intravenous administration |journal=Pharmaceutical Development and Technology |volume=17 |issue=4 |pages=443–456 |doi=10.3109/10837450.2010.546411 }}</ref> 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.<ref>{{Cite journal |pmid=33036563 |date=2020 |last1=Johann |first1=A. |last2=Ehlert |first2=U. |title=The study protocol: Neuroendocrinology and (Epi-) genetics of female reproductive transition phase mood disorder - an observational, longitudinal study from pregnancy to postpartum |journal=BMC Pregnancy and Childbirth |volume=20 |issue=1 |page=609 |doi=10.1186/s12884-020-03280-5 |doi-access=free |pmc=7545379 }}</ref>
In vitro studies show that dihydrokavain inhibits the cytochrome P450 enzymes CYP2C9 (IC<sub>50</sub> = 130.95 μM), CYP2C19 (IC<sub>50</sub> = 10.05 μM), and CYP3A4 (IC<sub>50</sub> = 78.59 μM), indicating potential drug interaction risks.<ref>{{Cite journal |pmid=15172113 |date=2004 |last1=Zedda |first1=M. |last2=Lepore |first2=G. |last3=Gadau |first3=S. |last4=Manca |first4=P. |last5=Farina |first5=V. |title=Morphological and functional changes induced by the amino acid analogue 3-nitrotyrosine in mouse neuroblastoma and rat glioma cell lines |journal=Neuroscience Letters |volume=363 |issue=2 |pages=190–193 |doi=10.1016/j.neulet.2004.04.008 }}</ref>
Dihydrokavain bears some structural similarity to the strobilurins and has some fungicidal activity.<ref name="Zakharychev-Kovalenko-1998">{{cite journal | last1=Zakharychev | first1=Vladimir V | last2=Kovalenko | first2=Leonid V | title=Natural compounds of the strobilurin series and their synthetic analogues as cell respiration inhibitors | journal=Russian Chemical Reviews | volume=67 | issue=6 | date=1998-06-30 | issn=0036-021X | doi=10.1070/rc1998v067n06abeh000426 | pages=535–544 | bibcode=1998RuCRv..67..535Z | s2cid=95676421}}</ref>
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.<ref>{{Cite journal |last1=Hadiza Muhammad Maiturare |last2=Mudassir Aliyu Magaji |last3=Muhammad Kabiru Dallatu |last4=Kabir Magaji Hamid |last5=Mustapha Umar Imam |last6=Ibrahim Malami |date=2022 |title=5,6-dehydrokawain improves glycaemic control by modulating AMPK target genes in Drosophila with a high-sucrose diet-induced hyperglycaemia |url=https://search.nal.usda.gov/discovery/search?query=lds35,contains,7719064-01nal_inst,AND&tab=LibraryCatalog&search_scope=MyInstitution&vid=01NAL_INST:MAIN&mode=advanced&offset=0 |journal=Phytomedicine Plus |language=English |volume=2 |issue=2 |pages=100261– |doi=10.1016/j.phyplu.2022.100261 |s2cid=247649601 |issn=2667-0313|doi-access=free }}</ref>
==References== {{Reflist|2}}
{{Kava}} {{Dopaminergics}} {{GABAAR PAMs}}
Category:Kavalactones Category:Anxiolytics Category:GABAA receptor positive allosteric modulators Category:Monoamine oxidase inhibitors