Target: GABAA receptor (positive allosteric modulator) – no IC₅₀/Ki/EC₅₀ values reported; at α1β2γ2L, 300 μM Kavain potentiated GABA EC₃ response by 170±23% [1]

The primary anxiolytic kavalactone Kavain's effects on human recombinant α1β2, β2η2L, αxβ2η2L, α1βxη2L, and α4β2δ γ-aminobutyric acid type A receptors (GABAAR) expressed in Xenopus laevis oocytes were studied using a two-electrode voltage clamp approach. Regardless of the makeup of the subunits, kavain positively regulates all receptors; however, the increase is larger for α4β2δ GABAAR than for α1β2η2L GABAAR. Flumazenil had no effect on the modulatory effects of kavain, suggesting that kavain does not increase GABAAR via the traditional benzodiazepine binding site. [1].

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In Vitro: Kavain (10–300 μM) concentration‑dependently enhanced GABA (10 μM, EC₃)-evoked currents at α1β2γ2L GABAA receptors, with 300 μM producing 170±23% potentiation (n=6). It had negligible intrinsic agonist activity (<1% of 10 mM GABA response at 300 μM) [1].
Kavain (300 μM) potentiated low‑concentration GABA responses at all tested receptor subtypes: α1β2, β2γ2L, αxβ2γ2L (x=1,2,3,5), α1βxγ2L (x=1,2,3) and α4β2δ, with no significant subtype selectivity (p>0.05, Tukey's test) [1].
At α1β2γ2L receptors, Kavain (300 μM) did not shift the GABA EC₅₀ (136 μM vs. 99 μM with kavain) nor increase maximal GABA response. At α4β2δ receptors, kavain (300 μM) increased the maximal GABA response by two‑fold (p<0.0001) without affecting GABA potency [1].
Kavain potentiation was insensitive to flumazenil (10 μM). Co‑application with diazepam (1 μM) produced less‑than‑additive enhancement (350±10% vs. expected 420%). Kavain slightly reduced etomidate (3 μM) potentiation (from 53±2.6% to 45±3.1% of maximal GABA, p<0.01) but did not affect etomidate (30 μM) direct activation. Kavain did not alter propofol (10 μM) potentiation but modestly reduced propofol (100 μM) direct activation (by 9%, p<0.01) [1].
At α1M236Wβ2γ2L and α1β2M286Wγ2L mutant receptors (which impair etomidate/propofol sensitivity), Kavain (300 μM) showed increased intrinsic agonist activity (63±5.2% and 96±5.8% of GABA EC₃ response, respectively) but potentiation of GABA EC₃ was unchanged vs. wild‑type. In contrast, at β3N265Mγ2L mutants (which abolish anaesthetic sensitivity), Kavain potentiation was significantly reduced from 260±18% (wild‑type α1β3γ2L) to 110±14% (mutant) (p<0.001), and its intrinsic activity was negligible (3.3±1.0%) [1].

Cell Assay: Human GABAA receptor subunits (α1-5, β1-3, γ2L, δ) were expressed in Xenopus laevis oocytes. cDNAs were linearized and mRNAs synthesized using T7 mMessage mMachine. Oocytes were isolated from anaesthetized female frogs, defolliculated with collagenase A, and healthy stage V‑VI oocytes were injected with 2‑10 ng of subunit mRNA mixtures (ratios: 1:1:3 for αβγ2L with β2; 10:1:10 for β1/β3; 5:1:5 for α4β2δ). Oocytes were incubated at 18 °C for 2‑5 days. Two‑electrode voltage‑clamp recordings were performed at a holding potential of −60 mV. Recording microelectrodes (0.2‑1.1 MΩ) were filled with 3 M KCl. Oocytes were continuously perfused with ND96 recording solution (96 mM NaCl, 2 mM KCl, 1 mM MgCl₂, 1.8 mM CaCl₂, 5 mM HEPES hemisodium, pH 7.4) at ~5 mL/min. GABA, etomidate and ZnCl₂ were dissolved in ND96; allopregnanolone, diazepam, DS2, flumazenil, propofol and Kavain were dissolved in DMSO (final DMSO concentration 0.8%). Data were acquired with PowerLab and LabChart. GABA concentration‑response curves were fitted to a monophasic Hill equation. Potentiation was calculated as (I_modulator - I_GABA)/I_GABA or as fold change. All experiments used at least two different oocyte batches [1].

[1]. Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors: Functional Characteristics and Molecular Mechanism. PLoS One. 2016 Jun 22;11(6):e0157700.

The chemical formula for DL-kavain is: https://www.chemicalbook.com/ProductChemicalPropertiesCB9738874_EN.htm. It is a glycine receptor antagonist. Neurocarvaline has been reported in pepper plants (such as black pepper, purple pepper, and alder), and relevant data are available. See also: Carvaline (note moved here).

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Additional Info: Kavain is one of six major kavalactones from Piper methysticum. Previous radioligand binding studies suggested interaction with GABAA receptors, but direct functional evidence was lacking. This study provides the first functional evidence that a single kavalactone directly potentiates GABAA receptors. The effect is flumazenil‑insensitive, ruling out the classical benzodiazepine site. The near‑complete loss of kavain potentiation at β3N265M mutant GABAA receptors indicates that kavain likely binds to the transmembrane anaesthetic binding cavities, similar to etomidate and propofol. However, unlike etomidate/propofol, kavain showed no subtype selectivity and its action was not impaired by α1M236W or β2M286W mutations. Kavain may have a greater impact on extrasynaptic δ‑containing GABAA receptors due to its ability to increase maximal GABA efficacy. These findings support the development of kavalactone‑derived anxiolytics [1].

C14H14O3

230.26

230.094

3155-48-4

3155-48-4 Kawain

5369129

White to yellow solid powder

1.2±0.1 g/cm3

432.6±45.0 °C at 760 mmHg

142-148ºC

184.6±23.3 °C

0.0±1.0 mmHg at 25°C

1.565

1.69

0

3

3

17

324

0

COC1=CC(=O)OC(C1)/C=C/C2=CC=CC=C2

XEAQIWGXBXCYFX-BQYQJAHWSA-N

InChI=1S/C14H14O3/c1-16-13-9-12(17-14(15)10-13)8-7-11-5-3-2-4-6-11/h2-8,10,12H,9H2,1H3/b8-7+

4-methoxy-2-[(E)-2-phenylethenyl]-2,3-dihydropyran-6-one

D,L-Kawin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~217.15 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.86 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)