Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator
Open accessAbstract
Zuranolone (SAGE-217) is a novel, synthetic, clinical stage neuroactive steroid GABAA receptor positive allosteric modulator designed with the pharmacokinetic properties to support oral daily dosing. In vitro, zuranolone enhanced GABAA receptor current at nine unique human recombinant receptor subtypes, including representative receptors for both synaptic (γ subunit-containing) and extrasynaptic (δ subunit-containing) configurations. At a representative synaptic subunit configuration, α1β2γ2, zuranolone potentiated GABA currents synergistically with the benzodiazepine diazepam, consistent with the non-competitive activity and distinct binding sites of the two classes of compounds at synaptic receptors. In a brain slice preparation, zuranolone produced a sustained increase in GABA currents consistent with metabotropic trafficking of GABAA receptors to the cell surface. In vivo, zuranolone exhibited potent activity, indicating its ability to modulate GABAA receptors in the central nervous system after oral dosing by protecting against chemo-convulsant seizures in a mouse model and enhancing electroencephalogram β-frequency power in rats. Together, these data establish zuranolone as a potent and efficacious neuroactive steroid GABAA receptor positive allosteric modulator with drug-like properties and CNS exposure in preclinical models. Recent clinical data support the therapeutic promise of neuroactive steroid GABAA receptor positive modulators for treating mood disorders; brexanolone is the first therapeutic approved specifically for the treatment of postpartum depression. Zuranolone is currently under clinical investigation for the treatment of major depressive episodes in major depressive disorder, postpartum depression, and bipolar depression.
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Self-citationExtrasynaptic GABA <sub>A</sub> Receptors: Form, Pharmacology, and Function
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Self-citationTrial of SAGE-217 in Patients with Major Depressive Disorder
Gunduz-Bruce, H., Silber, C., Kaul, I., Rothschild, A. J., Riesenberg, R., Sankoh, A. J., Li, H., Lasser, R., Zorumski, C. F., Rubinow, D. R., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1815981 · Cited by 232 · see citing works
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Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites.
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- Authors
- Althaus, A. L., Ackley, M. A., Belfort, G. M., Gee, S. M., Dai, J., Nguyen, D. P., Kazdoba, T. M., Modgil, A., Davies, P. A., Moss, S. J., Salituro, F. G., Hoffmann, E., Hammond, R. S., Robichaud, A. J., Quirk, M. C., & Doherty, J. J.
- Affiliations
- Sage Therapeutics (United States) (US)
- Tufts University (US)
- Corresponding author
- Althaus, Alison L.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 181
- Pages
- 108333
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC8265595
- OpenAlex
- W3088338988
- Cited by
- 135
- References
- 11
- Citations by year
- 2026: 21 · 2025: 15 · 2024: 36 · 2023: 29 · 2022: 14 · 2021: 18 · 2020: 2
- FWCI
- 7.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuropharmacology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Sage Therapeutics
- National Institute of Neurological Disorders and Stroke (R01NS108378, R21NS111338, R21NS111064, R01NS081986)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Keywords
- zuranolone, neurosteroids, GABAA receptor, positive allosteric modulators, GABA currents, extrasynaptic GABAA receptors, receptor trafficking, seizures, major depressive disorder, postpartum depression, bipolar depression, mood disorders
- MeSH terms
- Animals, Anticonvulsants, Antidepressive Agents, Binding Sites, Brain, Diazepam, Drug Synergism, Electroencephalography, gamma-Aminobutyric Acid, Hippocampus, Humans, Male, Pregnanes, Pregnanolone, Pyrazoles, Seizures, Steroids, Rats, Sprague-Dawley, Receptors, GABA, GABA Modulators, Mice, GABA-A Receptor Agonists
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