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| Preferred IUPAC name (6R)-6-[(E)-2-(2H-1,3-Benzodioxol-5-yl)ethen-1-yl]-4-methoxy-5,6-dihydro-2H-pyran-2-one | |
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| Properties | |
| C15H14O5 | |
| Molar mass | 274.272 g·mol−1 |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Methysticin is one of the six majorkavalactones found in thekava plant.[1] It enhances the activity of theGABAA receptor, acting as a positive modulator without affecting thebenzodiazepine binding site. This effect is attributed to structural features such as its angular lactone ring and is similar in strength to otherkavalactones likekavain anddihydromethysticin. Methysticin also induces the liver enzymeCYP1A1, which plays a role in thetoxification of benzo[a]pyrene into a highlycarcinogenicmetabolite, although such induction has not been observedin vivo in humans or animals. Additionally, methysticin is a mechanism-based inactivator ofCYP2C9, irreversibly inhibiting the enzyme through NADPH-dependent reactive intermediates, suggesting potential interactions with medications metabolized by CYP2C9.
It enhances the binding activity of the GABA_A receptor. Specifically, at a concentration of 0.1micromolar, (+)-methysticin increases the binding of the receptor ligand [3H]bicuculline methochloride by approximately 18% to 28%, indicating it acts as a positive modulator of the GABAA receptor. This modulatory effect is similar in strength to related kavapyrones such as (+)-kavain and (+)-dihydromethysticin. Importantly, methysticin's effect is not due to interaction with the benzodiazepine receptor, as it does not influence the binding of [3H]flunitrazepam, which is a benzodiazepine receptor ligand. Structural features, such as the angular lactone ring present in methysticin and other enolides, are crucial for this activity. Overall, methysticin enhances GABA_A receptor function through a mechanism distinct from that of benzodiazepines, contributing to the neuroactive properties of kava.[2]
Methysticin induces the function of the hepatic enzyme CYP1A1. This enzyme is involved in thetoxification ofbenzo[a]pyrene into(+)-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide, a highly carcinogenic substance. Another related compound is dihydromethysticin, which also induces the function of CYP1A1.[3][4][5] No report so far has described enhancement of CYP1A1 expression in animals or humans in vivo from any constituent of kava.[6]
It was studied for its effects oncytochrome P450 enzymes. It was found to strongly and irreversibly inhibitCYP2C9 in a time-, concentration-, and NADPH-dependent manner, with ~85% inhibition at 50 μM. Kinetic analysis revealed a KI of 13.32 μM, kinact of 0.054 min-1, and a half-life of inactivation around 12.8 minutes. The inhibition was partially prevented bysulfaphenazole (a CYP2C9 inhibitor), but not by antioxidants likecatalase orglutathione. Evidence suggests the involvement of reactive intermediates—a carbene (since K3Fe(CN)6 restored some activity) and an NADPH-dependent ortho-quinone trapped by glutathione.CYP1A2,CYP2C9, andCYP3A4 enzymes were involved in methysticinbioactivation. Overall, methysticin acts as a mechanism-based inactivator of CYP2C9 through reactive intermediate formation.[7]
