Target: [1]
Ganaxolone acts as a positive allosteric modulator of GABA_A receptors, binding to neurosteroid sites with highest affinity for synaptic δ-subunit-containing receptors (EC₅₀ = 0.28 μM for α1β2δ receptors).

In Vivo: [1]
In adult male rat anxiety models (elevated plus maze), acute intraperitoneal injection of Ganaxolone (10 mg/kg) increased open-arm exploration time by 75% (p<0.01) and reduced anxiety scores by 40% compared to vehicle controls.

In juvenile rat maternal separation models, chronic oral administration of Ganaxolone (5 mg/kg/day for 14 days) normalized stress-induced HPA axis dysregulation, reducing corticosterone levels by 35% (p<0.05) and reversing social interaction deficits. [2]

Animal Protocol: [1]
Acute anxiety studies: Ganaxolone was dissolved in 20% β-cyclodextrin and administered intraperitoneally at 5, 10, or 20 mg/kg 30 min pre-test. Behavioral assessments included elevated plus maze and open field tests.

Developmental studies: Oral suspension of Ganaxolone (2.5 or 5 mg/kg) in 0.5% methylcellulose was given daily via gavage to postnatal day 21-35 rats. Plasma and brain tissue collected 1 h post-final dose. [2]

Absorption, Distribution and Excretion
Following oral administration, peak plasma concentrations are reached within 2 to 3 hours. In healthy male subjects, after a single oral dose of radiolabeled ganassolon, 55% of the radioactive material was recovered from feces (2% of which was the original drug) and 18% from urine (containing no original drug). After oral administration, ganassolon and its metabolites are widely distributed in tissues, with a typical tissue/plasma ratio >5:1. Metabolism/Metabolites Ganassolon is primarily metabolized via CYP3A4/5, followed by CYP2B6, CYP2C19, and CYP2D6. Although data on ganassolon metabolism are lacking, a 16-OH metabolite produced via CYP3A4 has been identified as one of its major metabolites. Biological Half-Life The terminal half-life of ganassolon is 34 hours.

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ADME/Pharmacokinetics: [1]
30 minutes after intraperitoneal injection (10 mg/kg) in rats, the peak plasma concentration (C_max) reached 850 ng/mL; the brain/plasma ratio was 2.3, indicating that the drug preferentially accumulates in the central nervous system.
Oral bioavailability in juvenile rats was 92%, and the exposure was dose-dependent; the elimination half-life (t_½) was 1.8 hours. [2]

Effects During Pregnancy and Lactation
◉ Overview of use during lactation No clinical information has been published regarding the use of Ganasolone during lactation. However, a study by the manufacturer suggests that the drug concentration in breast milk appears to be low and is not expected to have any adverse effects on breastfed infants. ◉ Effects on breastfed infants No relevant published information was found as of the revision date. ◉ Effects on lactation and breast milk No relevant published information was found as of the revision date. Protein binding Ganasolone has a protein binding rate of approximately 99% in serum. Toxicity/Toxicokinetics: [1] No motor dysfunction was observed at anxiolytic doses (rotarod test, ≤20 mg/kg). Plasma protein binding rate >98%.
Long-term exposure did not lead to weight loss or organ toxicity; however, a dose of 5 mg/kg/day reduced play behavior in juvenile animals by 20% (p<0.05), indicating a dose-dependent behavioral effect. [2]

[1]. Psychopharmacology (Berl). 2015 Apr;232(8):1415-26.
[2]. Dev Psychobiol. 2024 Nov;66(7):e22554.

Additional information: [1]
Ganasolone is a synthetic analog of allogestrinone, used to treat refractory epilepsy and anxiety disorders. Phase II clinical trials showed that ganasolone reduced seizures in patients with CDKL5 deficiency by 35%.
It modulates GABAergic inhibition and does not produce tolerance similar to benzodiazepines. In 2022, ganasolone was approved by the FDA for the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency. [2]

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Ganasolone is a corticosteroid hormone.
Ganasolone is a Category 5 controlled substance under the U.S. Drug Enforcement Administration (DEA). Category 5 controlled substances are less likely to be abused than Category 4 controlled substances and mainly include preparations containing small amounts of specific anesthetics. It is a sedative.
Ganasolone is a 3β-methylated synthetic analog of allogestrinone (a metabolite of progesterone). Ganasolone belongs to a class of compounds called neurosteroids. Endogenous neurosteroids, including certain metabolites of progesterone and deoxycorticosterone, can bind potently and specifically to GABAA receptors, enhancing their inhibitory effects and thus possessing anxiolytic, analgesic, anticonvulsant, sedative, hypnotic, and anesthetic properties. Ganaxolone, similar to its endogenous counterpart, is a positive allosteric modulator of the GABAA receptor. In March 2022, the US FDA approved it under the brand name ZTALMY for the treatment of seizures associated with CDKL5 deficiency (CDD), becoming the first FDA-approved drug specifically for the treatment of CDD. In July 2023, Ganaxolone, under the same brand name, was approved by the European Medicines Agency (EMA) for the same indication. Ganaxolone is a positive modulator of the neuroactive steroid γ-aminobutyric acid (GABA) receptor. The mechanism of action of Ganaxolone is as a positive modulator of the GABA_A receptor.
Ganaxolone is a highly bioavailable synthetic analog of the neuroactive steroid allogeneic ketone and a positive allosteric modulator of the γ-aminobutyric acid (GABA) A receptor, exhibiting anxiolytic, sedative, antidepressant, and anticonvulsant activities. After oral administration, ganaxolone specifically targets and binds to the allosteric sites of the central nervous system (CNS) synaptic and extrasynaptic GABA_A receptor-chloride ion-carrier complex. This leads to increased chloride channel opening, membrane hyperpolarization, enhanced GABA's inhibitory effect on the CNS, and inhibition of neurotransmitter transmission. This can block the propagation of seizures and raise the seizure threshold.
Pharmaceutical Indications

Ganaxolone has been approved by the FDA for the treatment of cyclin-dependent kinase-like protein 5 (CDKL5) deficiency (CDD)-related seizures in patients 2 years of age and older. The EMA has also approved it as adjunctive therapy in patients aged 2 to 17 years, but it may continue to be used in patients 18 years of age and older. Ztalmy has been approved for adjunctive treatment of cyclin-dependent kinase-like 5 (CDKL5) deficiency-related seizures in patients aged 2 to 17 years. Ztalmy may also be used in patients 18 years of age and older. Treatment of Cyclin-Dependent Kinase-Like 5 Deficiency Mechanism of Action Ganaxurone belongs to a new class of neuroactive steroids, sometimes called "epalone," and is a potent and specific positive allosteric modulator of the gamma-aminobutyric acid type A (GABA_sub>A) receptor in the central nervous system (CNS). It binds to one of several potential binding sites of the GABA_sub>A receptor, all of which are different from the binding sites of benzodiazepines. By enhancing the inhibitory effect of the GABA_sub>A receptor, endogenous and exogenous neurosteroids have been shown to have anxiolytic, sedative, and anticonvulsant effects. While the exact mechanism of action of ganassolon in treating CDD-related seizures is unclear, its anticonvulsant effect is likely attributed to positive allosteric regulation of GABA_A receptors.
Pharmacodynamics
Like other neurosteroids, ganassolon lacks classic hormonal activity and appears to act directly by modulating GABA_A receptors. Similar to other antiepileptic drugs, ganassolon causes significant drowsiness and sedation—patients should be advised to exercise extra caution when operating heavy machinery (e.g., driving). Furthermore, antiepileptic drugs may increase the risk of suicidal behavior and ideation, although this risk has not been directly confirmed in patients taking ganassolon. Clinicians should weigh the risk of suicidal ideation or behavior against the risk of untreated disease when considering ganassolon treatment. Ganassolon's drug control class is currently under review by the U.S. Drug Enforcement Administration (DEA), but it appears to have some abuse potential. Clinicians should assess a patient's history of drug abuse before deciding to initiate ganassolon treatment.

C22H36O2

332.528

332.272

38398-32-2

6918305

Typically exists as solid at room temperature

1.036g/cm3

434.8ºC at 760mmHg

190-198C

185.4ºC

1.517

4.985

1

2

1

24

542

8

O([H])[C@]1(C([H])([H])[H])C([H])([H])C([H])([H])[C@@]2(C([H])([H])[H])[C@]([H])(C1([H])[H])C([H])([H])C([H])([H])[C@@]1([H])[C@]3([H])C([H])([H])C([H])([H])[C@]([H])(C(C([H])([H])[H])=O)[C@@]3(C([H])([H])[H])C([H])([H])C([H])([H])[C@@]12[H]

PGTVWKLGGCQMBR-FLBATMFCSA-N

InChI=1S/C22H36O2/c1-14(23)17-7-8-18-16-6-5-15-13-20(2,24)11-12-21(15,3)19(16)9-10-22(17,18)4/h15-19,24H,5-13H2,1-4H3/t15-,16-,17+,18-,19-,20+,21-,22+/m0/s1

1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

CCD-1042; CCD 1042; C1042; GANAXOLONE; 38398-32-2; 3alpha-Hydroxy-3beta-methyl-5alpha-pregnan-20-one; ganaxolona; UNII-98WI44OHIQ; 98WI44OHIQ; DTXSID6046503; CCD1042; CCD-1042; Ztalmy Ganaxolone

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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