A Pharmacological Characterization of Novel Neuroactive Steroid Modulators of GABA
A Pharmacological Characterization of Novel Neuroactive Steroid Modulators of GABAA Receptors 124.21 Mike A. Ackley, Gabriel Martinez-Botella, Gabriel M. Belfort, Carlos M. Loya, Francesco G. Salituro, Albert J. Robichaud & James J. Doherty SAGE Therapeutics, Cambridge, MA Overview SGE-516 is a PAM of GABAA receptors with similar pharmacology to SAGE-547 SGE-516 exhibits minimal undesired off-target activity • GABAA receptors are pentamers with a preferred stoichiometry of two α, two β and one other subunit such as γ or δ Broad ligand selectivity panel S ig m a • The GABAA receptor is a classical CNS target for therapeutic drugs such as benzodiazepines, barbiturates and propofol. T a rg e t • Benzodiazepines bind to the interface of the GABAA α and γ subunits and are thus limited in efficacy as they only modulate γcontaining receptors • γ-containing receptors predominate at synaptic sites, whilst a large population of extra-synaptic GABAA receptors typically contain the δ-subunit 0 5 1 0 7 0 5 2 5 0 GABAA Nuclear Hormone receptors 5 2 0 2 5 1 1 0 SGE-516 potentiates currents through δ-containing GABAA receptors 0 T a rg e t Hypothesis Targeting both synaptic and extra-synaptic GABAA receptors is likely to confer enhanced therapeutic efficacy in seizure indications that are refractory to benzodiazepines PXR PR PPARg PPARd PPARa LXRa GR FXR ERa CAR3 Ahr AR 5 SGE-516 modulates channel gating % In h ib it io n F o ld A c tiv a tio n No significant activity was observed at cardiac ion channels Conclusions SAGE compounds show sustained efficacy at δ-containing GABAA receptors • We have developed a series of novel neuroactive steroid compounds with a range of pharmacologies and pharmacokinetic properties suitable for in vivo testing • Unlike benzodiazepines, SAGE compounds strongly potentiate GABA currents at both representative synaptic (α1β2γ2) and extrasynaptic (α4β3δ) GABAA receptors • SAGE allosteric modulators likely affect gating of the channel rather than affecting the affinity of the orthosteric ligand, but they do not directly activate the GABAA receptor Differentiation from Propofol Differentiation from Benzodiazepines www.sagerx.com/posters/poster2.pdf • Propofol potentiates peak, but not steady state currents (Houston et al, 2012, J.Neurosci 32:11 3887-3897) • This effect is consistent with the ability of SAGE compounds to modulate tonic currents (see poster 699.21) • In contrast to propofol, SAGE compounds potentiate steady state current at GABAA α4β3δ subunits, commensurate with their desired physiological effect • As such, SAGE compounds such as SGE-516 may represent novel therapies for benzodiazepine-refractory seizure indications
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