| In Vitro | In vitro activity: SAGE-217 is a novel and potent GABAA receptor modulator/agonist at both synaptic and extrasynaptic receptor subtypes with EC50s of 296 and 163 nM for α1β2γ2 and α4β3δ GABAA receptors, respectively, and with excellent oral DMPK properties. SAGE-217 has completed a phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) clinical trial and is currently being studied in parallel phase 2 clinical trials for the treatment of postpartum depression (PPD), major depressive disorder (MDD), and essential tremor (ET). Certain classes of neuroactive steroids (NASs) are positive allosteric modulators (PAM) of synaptic and extrasynaptic GABAA receptors.
Kinase Assay: Zuranolone (SAGE-217) is a novel and potent GABAA receptor agonist with EC50s of 296 and 163 nM for α1β2γ2 and α4β3δ GABAA receptors, respectively.
Cell Assay: SAGE-217 is a novel and potent GABAA receptor modulator/agonist at both synaptic and extrasynaptic receptor subtypes with EC50s of 296 and 163 nM for α1β2γ2 and α4β3δ GABAA receptors, respectively. Cortices are rapidly removed following decapitation of euthanization by carbon dioxideasphyxiation Sprague-Dawley rats (200 to 250 g). The cortices are homogenized in 10 volumes of ice-cold 0.32 M sucrose using a glass/teflon homogenizer and centrifuged at 1500× g for 10 min at 4°C. Aliquots (100 μL) of the membrane suspensions are incubated with 3 nM [35S]-TBPS and 5 μL aliquots of SAGE-217 dissolved in DMSO (final 0.5%) in the presence of 5 μM GABA. The incubation is brought to a final volume of 1.0 mL with buffer. Following a 90 min incubation at room temp, the assays are terminated by filtration through glass fiber filters using a cell harvester and rinsed three times with ice-cold buffer. Filter bound radioactivity is measured by liquid scintillation spectrometry |
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| In Vivo | Acute administration of SAGE-217 (0.3 to 10 mg/kg, ip) effectively reduces pentylenetretazol (PTZ)-induced seizures in mice (MECplasma=85 nM) as well as produces a dose-dependent anticonvulsant effect in the mouse 6 Hz electrical stimulation model. In the rat lithium-pilocarpine model of status epilepticus (SE), SAGE-217 (0.3 to 5 mg, iv) abolishes both behavioral and electrographic seizure activity, even when administered 60 min after induction of SE. Additional PK studies of SAGE-217 in dog show low clearance (<10% of hepatic blood flow), resulting in excellent oral bioavailability (F=68%) |
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| Animal model | In vivo pharmacokinetic parameters are determined in male Sprague Dawley rats (of 200 to 300 g in weight), male CD-1 mice (15 to 25 g in weight), and male beagle dogs (8 to 12 kg in weight). Doses of SAGE-217 for intravenous (IV) and oral administration (PO) are formulated as solutions in SBECD. SAGE-217 is dosed IV (5 mg/kg, 2.5 mL/kg) or by oral gavage (20 mg/kg, 10 mL/kg). Animals in the IV group are sampled at 0.083, 0.25, 1, 2, 4, and 8 hours post-dose and PO animals are sampled at 0.5, 1, 2, 4, and 8 hours post dose. Brain samples from the IV group are also collected at 1 hour post-dose. Blood samples are collected into tubes treated with K2-EDTA, then centrifuged at 2000 g at 4°C for 15 min. Plasma is isolated and frozen at -70°C until extraction. |
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| Formulation & Dosage | SAGE-217 is dosed IV (5 mg/kg, 2.5 mL/kg) or by oral gavage (20 mg/kg, 10 mL/kg). |
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| References | J Med Chem. 2017 Sep 28;60(18):7810-7819. |
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