With EC50s of 296 and 163 nM for α1β2η2 and α4β3δ GABAA receptors, respectively, zuranolone is a strong agonist of GABAA receptors. Phase 2 clinical trials investigating zuranolone are presently being conducted in parallel to treat major depressive disorder (MDD) and postpartum depression (PPD). In a cardiac panel consisting of eight significant cardiac ion channels, zuranolone exhibits >30 μM inhibition. Only binding at the glycine (57%), sigma (88%), and transient receptor potential vanilloid 1 (TRPV1, 95%) is observed at 10 μM concentration of Zuranolone[1].

Pentylenetretazol (PTZ)-induced seizures in mice (MECplasma=85 nM) are effectively reduced by acute administration of Zuranolone (0.3 to 10 mg/kg, ip). In addition, a dose-dependent anticonvulsant effect is produced in the mouse 6 Hz electrical stimulation model. Even when given 60 minutes after the onset of status epilepticus (SE), Zuranolone (0.3 to 5 mg, iv) completely eliminates both behavioral and electrographic seizure activity in the rat model of SE. Further PK studies on dogs with Zuranolone demonstrate excellent oral bioavailability (F=68%) due to low clearance (< 10% of hepatic blood flow)[1].

Absorption, Distribution and Excretion
Following oral administration, peak zuranolone concentrations occur at 5 to 6 hours (Tmax). The absolute bioavailability of zuranolone was not evaluated. Zuranolone exposure (Cmax and AUC) increased approximately dose proportionally with doses ranging from 30 mg to 60 mg (1.2 times the recommended dosage of zuranolone) with a moderate-fat meal (700 calories; 30% fat). Once-daily administration of Zuranolone resulted in an accumulation of approximately 1.5-fold in systemic exposures and a steady state was achieved in 3 to 5 days. Following administration of 30 mg of zuranolone to healthy subjects, the Cmax increased by approximately 3.5-fold, and the AUClast increased by approximately 1.8-fold with a low-fat meal (400 to 500 calories, 25% fat) compared to fasted conditions. The Cmax increased by approximately 4.3-fold and the AUClast increased by approximately 2-fold with a high-fat meal (800 to 1,000 calories, 50% fat) compared to fasted conditions. The Tmax was not impacted by food.
Following oral administration of radiolabeled zuranolone, 45% of the dose was recovered in urine as metabolites with negligible unchanged zuranolone and 41% in feces as metabolites with less than 2% as unchanged zuranolone.
The volume of distribution of zuranolone following oral administration is greater than 500 L.
The mean apparent clearance (CL/F) of zuranolone is 33 L/h.

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Metabolism / Metabolites
Zuranolone undergoes extensive metabolism, with CYP3A4 identified as a primary enzyme involved. There were no circulating human metabolites greater than 10% of total drug-related materials and none are considered to contribute to the therapeutic effects of zuranolone.

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Biological Half-Life
The terminal half-life of zuranolone is approximately 19.7 to 24.6 hours in the adult population.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because of the low amounts of zuranolone in milk, it would not be expected to cause any adverse effects in breastfed infants. If zuranolone is required by the mother, it is not a reason to discontinue breastfeeding. Until more data are available, zuranolone should be used with careful infant monitoring for excessive sedation during breastfeeding, especially with higher dosages and in newborn and preterm infants.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
In a manufacturer-sponsored study, 14 healthy lactating women who were 12 or more weeks postpartum and treated with oral administration of 30 mg of zuranolone daily for 14 days collected milk samples from 3 days before to day 5 of treatment. There was a mean decrease of 41.2 mL or 8.3% in milk volume collected over days 3 to 5 of treatment compared with pretreatment baseline. However, this decrease could be an artifact of the study design, because participants were told to stop breastfeeding and pump their milk during the study. Other factors could have been at play, also.

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Protein Binding
The mean blood-to-plasma concentration ratio ranged from 0.54 to 0.58. Plasma protein binding is greater than 99.5%.

[1]. Martinez Botella G, et al. Neuroactive Steroids. 2. 3α-Hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5β-pregnan-20-one: A Clinical Next Generation Neuroactive Steroid Positive Allosteric Modulator of the (γ-Aminobutyric Acid)A Receptor. J Med Chem. 2017 Sep 28;60(18):7810-7819

Zuranolone is a 3-hydroxy steroid that is 5beta-19-norpregnane substituted by hydroxy, methyl, oxo, and 4-cyano-1H-pyrazol-1-yl groups at positions 3, 3, 20 and 21, respectively. It is a positive allosteric modulator of GABAA receptor developed by Sage Therapeutics and Biogen for the treatment of postpartum depression in adults. It has a role as an antidepressant, a GABA modulator and an anticonvulsant. It is a nitrile, a member of pyrazoles, a 3-hydroxy steroid and a 20-oxo steroid.
Zuranolone is a DEA Schedule IV controlled substance. Substances in the DEA Schedule IV have a low potential for abuse relative to substances in Schedule III. It is a Depressants substance.
Zuranolone is a neuroactive steroid that acts as a positive allosteric modulator of the GABAA receptors. Unlike other more common GABAA positive allosteric modulators on the market like benzodiazepines, zuranolone can modulate both synaptic and extrasynaptic GABAA conductance due to binding to a non-benzodiazepine site on the receptor. Zuranolone was designed with a pharmacological profile of a neuroactive steroid in mind while also possessing a pharmacokinetics profile of an oral, once-daily dosing formulation. Zuranolone was approved by the FDA on August 4th, 2023, and it is currently the only approved treatment for women with postpartum depression. This approval was based on favorable results from 2 phase 3 clinical trials.
Zuranolone is a Neuroactive Steroid Gamma-Aminobutyric Acid A Receptor Positive Modulator. The mechanism of action of zuranolone is as a GABA A Receptor Positive Modulator.

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Drug Indication
Zuranolone is indicated for the treatment of postpartum depression (PPD) in adults.
Treatment of postpartum depression

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Mechanism of Action
The mechanism of action of zuranolone in the treatment of PPD is not fully understood but is thought to be related to its positive allosteric modulation of GABA_A receptors. Unlike benzodiazepines, another class of GABA_A positive modulators, zuranolone binds to the α/β subunit interface presented in all GABA_A receptors instead of the α/γ subunit interface. Therefore, zuranolone can bind to both synaptic GABA_A receptors, composed of 2α2βγ subunits, and extrasynaptic GABA_A receptors, composed of 2α2βδ subunits.

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Pharmacodynamics
At two times the maximum recommended dose, zuranolone does not cause clinically significant QTc interval prolongation. Co-administration of repeated 50 mg daily doses of zuranolone with alcohol or alprazolam led to impairment in psychomotor performance. Zuranolone exhibited an EC₅₀ of 430 nM and 118 nM at the α1β2γ2 and α4β3δ GABA_A receptors respectively, the two most abundant synaptic and extrasynaptic receptors in the brain. Therefore, zuranolone can potentiate both phasic and tonic postsynaptic currents associated with modulation of the synaptic and extrasynaptic GABA_A receptors respectively. Since tonic current can produce a larger inhibitory effect compared to phasic current, the ability of zuranolone to modulate the tonic current provides a greater opportunity to enhance GABA conductance.

C25H35N3O2

409.564306497574

409.272

1632051-40-1

1632051-40-1;DXN51401;

86294073

Typically exists as solid at room temperature

4.5

1

4

3

30

746

8

C[C@]1(CC[C@H]2[C@@H](C1)CC[C@@H]3[C@@H]2CC[C@]4([C@H]3CC[C@@H]4C(=O)CN5C=C(C=N5)C#N)C)O

HARRKNSQXBRBGZ-GVKWWOCJSA-N

InChI=1S/C25H35N3O2/c1-24(30)9-7-18-17(11-24)3-4-20-19(18)8-10-25(2)21(20)5-6-22(25)23(29)15-28-14-16(12-26)13-27-28/h13-14,17-22,30H,3-11,15H2,1-2H3/t17-,18+,19-,20-,21+,22-,24-,25+/m1/s1

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)

Solubility in Formulation 1: 2.5 mg/mL (6.10 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (6.10 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 (6.10 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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Solubility in Formulation 4: 2.5 mg/mL (6.10 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
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 5: ≥ 2.5 mg/mL (6.10 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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