SAGE-217), a Selective Neuroactive Steroid GABAA Receptor Positive Allosteric Modulator
Neuropharmacology 181 (2020) 108333 Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator Alison L. Althaus a,*, Michael A. Ackley a, Gabriel M. Belfort a, Steven M. Gee a, Jing Dai a, David P. Nguyen a, Tatiana M. Kazdoba a, Amit Modgil b, Paul A. Davies b, Stephen J. Moss b, Francesco G. Salituro a, Ethan Hoffmann a, Rebecca S. Hammond a, Albert J. Robichaud a, Michael C. Quirk a, James J. Doherty a a Research and Nonclinical Development, Sage Therapeutics, Inc., Cambridge, MA, USA b Department of Neuroscience, Tufts University, Boston, MA, USA ARTICLE INFO ABSTRACT Keywords: Zuranolone (SAGE-217) is a novel, synthetic, clinical stage neuroactive steroid GABAA receptor positive allosteric Neuroactive steroid modulator designed with the pharmacokinetic properties to support oral daily dosing. In vitro, zuranolone GABAA receptor enhanced GABAA receptor current at nine unique human recombinant receptor subtypes, including represen Positive allosteric modulator tative receptors for both synaptic (γ subunit-containing) and extrasynaptic (δ subunit-containing) configurations. At a representative synaptic subunit configuration,α 1β2γ2, 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 traffickingof 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.
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