GABAA receptor (IC50 = 1.15 μM)

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].

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]

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]

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.

mouse LD50 intraperitoneal 8980 ug/kg Current Toxicology., 1(199), 1993
mouse LDLo subcutaneous 1600 ug/kg BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD Journal of the American Pharmaceutical Association., 23(98), 1934
mouse LD50 intracrebral 10 ug/kg BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD Toxicology Letters., 60(289), 1992 [PMID:1375788]
dog LDLo subcutaneous 1100 ug/kg Ueber die Wirkung Verschiedener Gifte Auf Vogel, Dissertation, Forchheimer, L., Pharmakologischen Institut der Universitat Wurzburg, Fed. Rep. Ger., 1931, -(-), 1931
rabbit LDLo subcutaneous 1350 ug/kg Ueber die Wirkung Verschiedener Gifte Auf Vogel, Dissertation, Forchheimer, L., Pharmakologischen Institut der Universitat Wurzburg, Fed. Rep. Ger., 1931, -(-), 1931

[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.

Picrotoxinin is a picrotoxane sesquiterpenoid that is 3a,4,5,6,7,7a-hexahydro-1H-indene-3,7-dicarboxylic acid which is substituted at positions 3a, 6, and 7a by methyl, isopropenyl, and hydroxy groups, respectively; in which the double bond at position 2-3 has been epoxidised; and in which the carboxy groups at positions 3 and 7 have undergone gamma-lactone formation by O-alkylation to positions 4 and 5, respectively. A component of picrotoxin. It has a role as a plant metabolite, a GABA antagonist and a serotonergic antagonist. It is an organic heteropentacyclic compound, an epoxide, a tertiary alcohol, a gamma-lactone and a picrotoxane sesquiterpenoid.
Picrotoxinin has been reported in Anamirta cocculus and Picrodendron baccatum with data available.

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Anxiolytics and anticonvulsants generally positively modulate the action of GABA, whereas many convulsants (including the chloride channel blocker picrotoxinin) negatively modulate the action of GABA on GABAA receptors. Like picrotoxinin, bilobalide and ginkgolide B, active constituents of Ginkgo biloba, have been shown to negatively modulate the action of GABA at α1β2γ2L GABAA receptors. However, unlike picrotoxinin, bilobalide and ginkgolide B are not known to cause convulsions. We have assessed the action of bilobalide, ginkgolide B and picrotoxinin on a range of GABAA modulators (etomidate, loreclezole, propofol, thiopentone sodium, diazepam, and allopregnanolone), using two-electrode voltage clamp electrophysiology at recombinant α1β2γ2L GABAA receptors expressed in Xenopus oocytes. The results indicate that bilobalide and ginkgolide B differ from picrotoxinin in their ability to inhibit the actions of a range of these structurally diverse GABAA positive modulators consistent with these modulators acting on a multiplicity of active sites associated with GABAA receptors. In the presence GABA, ginkgolide B was more potent than bilobalide in inhibiting the GABA-potentiating effect of propofol, equipotent against loreclezole and allopregnanolone, and less potent against etomidate, diazepam, and thiopentone sodium. This indicates that in comparison to picrotoxinin, bilobalide and ginkgolide B differ in their effects on the different modulators.[1]

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.)