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