GABAA receptor (IC50 = 1.15 μM)
Picrotoxinin targets the GABAA receptor chloride channel. It acts as a noncompetitive antagonist, blocking the chloride ion channel associated with the GABAA receptor. It has an IC50 of 1.15 µM at the recombinant α1β2γ2L receptor isoform. By inhibiting GABAergic signaling, it induces convulsions and has been used as a tool to study GABA receptor function. It is also an agonist of taste 2 receptor member 14 (TAS2R14).

In the presence of EC5 GABA at α1β2γ2L GABAA receptors, picrotoxinin (0.001 μM-1 mM; 60-90 s) suppresses the activity of GABAA receptors and modifies GABAA modulators [1].
Picrotoxinin demonstrates potent inhibition of GABAA receptor function in vitro with an IC50 of 1.15 µM at the recombinant α1β2γ2L receptor isoform. Its activity is assessed by electrophysiological recordings in Xenopus oocytes or mammalian cells expressing recombinant GABAA receptors. It is used as a tool to study GABAergic signaling and to evaluate anticonvulsant agents. It also acts as an agonist of TAS2R14 in bitter receptor screening assays.

Two strains of mice were shown to possess a differential sensitivity to picrotoxinin-induced convulsions; picrotoxinin elicited both tonic and clonic seizures at lower doses in the DBA/2J (DBA) strain compared to the BALB/c ByJ (BALB) strain. Less protection of picrotoxinin-induced tonic seizures was afforded by pentobarbital in the DBA strain. Biochemical studies revealed that picrotoxin inhibited36Cl− efflux from forebrain synaptoneurosomes only in the DBA strain. In addition, picrotoxin inhibited pentobarbital-induced36Cl− efflux to a greater extent in the DBA strain. No differences were observed in the binding of [3H]muscimol or [3H]t-butylbicyclophosphorothionate (TBPS) to forebrain homogenates, while pentobarbital was a less potent inhibitor of [35S]TBPS binding in the DBA strain. These findings suggest a genetic basis for the behavioral differences in convulsant sensitivity as well as for the neurochemical differences in allosteric coupling between convulsant and depressant/anticonvulsant sites associated with the GABA receptor-gated Cl− channel.[2]
Picrotoxinin has been used in vivo to induce convulsions in animal models. It is used in pharmacological and neurotoxicological research to probe GABAergic signaling and evaluate anticonvulsant agents. Its potent central nervous system activity makes it a valuable research compound in neuroscience, receptor pharmacology, and toxicology studies.

Recombinant α1β2γ2L GABAA receptors were also tested with increasing concentrations of picrotoxinin, bilobalide and ginkgolide B (0.001 µM to 1 mM) in the presence of EC50 GABA. In addition, antagonists (picrotoxinin, bilobalide and ginkgolide B) were used to probe for receptor activation for both GABA-mimetic and GABA-modulatory actions of positive modulators at α1β2γ2L GABA receptors. For GABA-modulatory inhibition curves, a range of antagonist concentrations was co-applied with 5 μM GABA (~EC5 GABA) and positive modulators at EC50 concentrations. The co-application of 60 s was of sufficient duration to ensure the complete effect of picrotoxinin, bilobalide and ginkgolide B. For GABA-mimetic inhibition curves, a range of antagonist concentrations was co-applied with the positive modulators at EC50 concentrations. The co-application of 90 s was of sufficient duration to ensure the complete effect of picrotoxinin, bilobalide and ginkgolide B. A washout period of 3–5 min was allowed between each application in order to prevent receptor desensitisation and to ensure that the baseline currents of oocytes were fully recovered.[1]
GABAA receptor chloride channel assays are performed using Xenopus oocytes or mammalian cells expressing recombinant GABAA receptor subunits (α1β2γ2L). Two-electrode voltage clamp or patch-clamp electrophysiology is used to record GABA-induced chloride currents. Picrotoxinin is applied at varying concentrations, and inhibition of GABA-induced currents is measured. IC50 values are determined by non-linear regression analysis. Each concentration is tested in multiple cells. TAS2R14 activation assays are performed using calcium imaging in cells expressing the receptor.

Cell viability assay [1]
Cell Types: Xenopus laevis oocytes
Tested Concentrations: 0.001 µM-1 mM
Incubation Duration: 60 and 90 seconds
Experimental Results: Dose-dependent inhibition of GABAA receptors, IC50 is 1.15 µM, comparable to similar drugs demonstrated the strongest activity than bilobalide and ginkgolide B. Inhibition of etomidate, propofol, diazepam, thiopental, lorracozole and isopropanol at α1β2γ2L GABAA receptors in the presence of EC5 GABA Progesterone, IC50 is 0.55, 0.49, 0.35-0.36, 0.50, 0.14 and 0.44 μM respectively.
Cellular GABAA receptor inhibition is evaluated in neuronal cell lines or primary neuronal cultures. Cells are cultured in appropriate media and treated with Picrotoxinin at various concentrations (0.1-100 µM). GABA-induced chloride influx is measured using fluorescent chloride indicators or by electrophysiological recording. Cell viability is assessed using MTT or LDH assays. Each experiment includes known GABAA receptor antagonists (e.g., bicuculline, picrotoxin) as positive controls.

In vivo studies are conducted in rodent models to evaluate convulsant activity and anticonvulsant agents. Picrotoxinin is administered intraperitoneally or intravenously at doses determined by preclinical studies. Seizure activity is monitored by behavioral observation (e.g., Racine scale). EEG recordings may be performed to measure seizure activity. Anticonvulsant agents are evaluated for their ability to prevent Picrotoxinin-induced seizures. Sample sizes typically range from 6-10 animals per group.

Picrotoxinin has a molecular weight of 292.28 g/mol and a molecular formula of C15H16O6. It is a hydroxylated fatty acid. Appearance: white powder. Storage: desiccate at -20°C. Purity: typically min. 95%. It is the active sesquiterpenoid component of picrotoxin, a plant-derived neurotoxin.

The intraperitoneal LD50 in mice was 8980 ug/kg, Contemporary Toxicology, 1(199), 1993. The subcutaneous LD50 in mice was 1600 ug/kg, Behavioral Studies: Seizures or Effects on the Epilepsy Threshold, JAMA, 23(98), 1934. The intracerebral LD50 in mice was 10 ug/kg, Behavioral Studies: Seizures or Effects on the Epilepsy Threshold, Toxicology Letters, 60(289), 1992 [PMID:1375788]. The subcutaneous LD50 in dogs was 1100 ug/kg, The Effects of Different Gifts on Birds, doctoral dissertation, Forchheimer, L., Institute of Pharmacology, University of Würzburg, Federal Reserve. German representative, 1931, -(-), 1931
Rabbit LDLo subcutaneous 1350 ug/kg Ueber die Wirkung Verschiedener Gifte Auf Vogel, paper, Forchheimer, L., Institute of Pharmacology, University of Würzburg, Fed. German Member of Parliament, 1931, -(-), 1931
Picrotoxinin is a potent neurotoxin. It induces convulsions and is used as a research tool. It is not intended for human use. Standard safety precautions for handling neurotoxins should be followed. Appropriate personal protective equipment should be used when handling this compound. No clinical trials have been reported.

[1]. Effects of bilobalide, ginkgolide B and picrotoxinin on GABAA receptor modulation by structurally diverse positive modulators. Eur J Pharmacol. 2017 Jul 5;806:83-90.

[2]. Differential seizure sensitivities to picrotoxinin in two inbred strains of mice (DBA/2J and BALB/c ByJ): parallel changes in GABA receptor-mediated chloride flux and receptor binding. Brain Res . 1989 Feb 27;481(1):169-74.

Matrine toxin is a matrine sesquiterpene compound with the structure 3a,4,5,6,7,7a-hexahydro-1H-indene-3,7-dicarboxylic acid, in which the 3a, 6, and 7a positions are substituted with methyl, isopropenyl, and hydroxyl groups, respectively; the double bond at positions 2-3 is epoxidized; and the carboxyl groups at positions 3 and 7 form γ-lactones with those at positions 4 and 5 via O-alkylation reactions, respectively. Matrine toxin is a component of matrine toxin. It is a plant metabolite with GABA antagonist and serotonin antagonist functions. It is an organic heteropentacyclic compound belonging to the epoxide, tertiary alcohol, γ-lactone, and bitter sesquiterpene class of compounds. Bitter sesquiterpenes have been reported to exist in custard apple (Anamirta cocculus) and strychnine (Picrodendron baccatum), and relevant data are available.

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Anxiolytics and anticonvulsants typically positively modulate the action of GABA, while many convulsant drugs (including the chloride channel blocker ginsenoside) negatively modulate the action of GABA on GABAA receptors. Similar to ginsenoside, the active components ginkgolides and ginkgolides B from Ginkgo biloba leaves have also been shown to negatively modulate the action of GABA on α1β2γ2L GABAA receptors. However, unlike ginsenoside, ginkgolides and ginkgolides B have not yet been found to induce convulsions. We used a two-electrode voltage-clamp electrophysiology technique to evaluate the effects of ginkgolides, ginkgolides B, and matrine toxin on a series of GABAA receptor modulators (etomidate, lorifol, propofol, thiopental sodium, diazepam, and allogenein) on recombinant α1β2γ2L GABAA receptors expressed in Xenopus laevis oocytes. The results showed that, unlike matrine toxin, ginkgolide and ginkgolide B had different abilities to inhibit the positive regulation of these structurally different GABAA receptors, which is consistent with the mechanism by which these regulators act on multiple active sites of GABAA receptors. In the presence of GABA, ginkgolide B had a stronger ability to inhibit the propofol-GABA-enhancing effect than ginkgolide, and its inhibitory effects on loracazole and allogenein were comparable, while its inhibitory effects on etomidate, diazepam and thiopental sodium were weaker. This indicates that, compared with matrine toxin, ginkgolide and ginkgolide B have different effects on different regulators. [1]
Picrotoxinin is also known as (-)-Picrotoxinin. It is the active sesquiterpenoid component of picrotoxin from Anamirta cocculus. It acts as a noncompetitive antagonist of the GABAA receptor chloride channel with an IC50 of 1.15 µM. It is used in neuroscience research to probe GABAergic signaling. No clinical trials or regulatory approvals have been reported. The compound is for research use only.

C15H16O6

292.29

292.095

C, 61.64; H, 5.52; O, 32.84

17617-45-7

Picrotoxin;124-87-8

442292

White to off-white solid powder

1.52g/cm3

551.6ºC at 760mmHg

203-205ºC

214ºC

1.82E-14mmHg at 25°C

1.625

0.5

1

6

1

21

642

8

CC(=C)[C@@H]1[C@@H]2[C@@H]3[C@@]4([C@]([C@H]1C(=O)O2)(C[C@@H]5[C@]4(O5)C(=O)O3)O)C

PIMZUZSSNYHVCU-YKWPQBAZSA-N

InChI=1S/C15H16O6/c1-5(2)7-8-11(16)19-9(7)10-13(3)14(8,18)4-6-15(13,21-6)12(17)20-10/h6-10,18H,1,4H2,2-3H3/t6-,7+,8-,9-,10-,13-,14-,15+/m1/s1

(1R,3R,5S,8S,9R,12S,13R,14R)-1-hydroxy-13-methyl-14-prop-1-en-2-yl-4,7,10-trioxapentacyclo[6.4.1.19,12.03,5.05,13]tetradecane-6,11-dione

NSC-129537; picrotoxinin; Picrotoxinine; (-)-Picrotoxinin; 17617-45-7; UNII-9K011NUF0R; 9K011NUF0R; CHEBI:8206; Picrotoxin (Part b); NSC 129537; Picrotoxinin

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 : ~100 mg/mL (~342.14 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.55 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (8.55 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (8.55 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.)