The family of GABAA receptors, broadly expressed in the brain, are pentameric ion channels primarily composed of two alpha subunits (α1-α6), two beta subunits (β1-β3) and one additional subunit (γ1-γ3, δ, ε, π, or θ). GABA, acting via the GABAA receptor, can influence a wide range of brain circuits that are central to a variety of behavioral states, such as anxiety levels, seizures, sleep, vigilance, and memory. SAGE-217, belonging to neuroactive steroids (NASs), is a positive allosteric modulators (PAM) of synaptic and extrasynaptic GABAA receptors, with EC50s of 296 and 163 nM for α1β2γ2 and α4β3δ GABAA receptors, respectively. In vitro CYP inhibition (IC50) was >30 μM for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP2B6. Further, SAGE-217 showed >30 μM inhibition in a cardiac panel of eight relevant cardiac ion channels. At 10 μM concentrations of SAGE-217, only binding at the glycine (57%), sigma receptors (88%), and inhibition of the transient receptor potential vanilloid 1 (TRPV1, 95%) was noted. Acute administration of 3 (0.3–10 mg/kg, ip) effectively reduced pentylenetretazol (PTZ)-induced seizures in mice (MECplasma = 85 nM; SAGE-217 (0.3–3 mg/kg, ip)) as well as producing 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 (0.3–5 mg, iv) abolished both behavioral and electrographic seizure activity, even when administered 60 min after induction of SE. Furthermore, SAGE-217 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)[1].
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