A Pharmacological Characterization of Novel Neuroactive Steroid Modulators of
NMDA Receptors
37.12
Mike A. Ackley, Gabriel M. Belfort, Gabriel Martinez-Botella, Francesco G. Salituro, Albert J. Robichaud & James J. Doherty
SAGE Therapeutics, Cambridge, MA
Expression of hGluN1/hGluN2x subunits in Oocytes
• NMDA receptors play a key role in neuroplasticity and have
been implicated in the pathophysiology of numerous
neuropsychiatric and neurodegenerative diseases making
them key targets for drug development
0 .5 0
0 .2 5
0 .0 1
0 .1
1
10
100
1000
P 12 0~150 day
180
1 u M S G E -2 0 1
V e h ic le
160
1  M S G E -2 0 1
V e h ic le
160
140
140
120
120
100
100
80
80
TBS
60
0
GluN2B selective
T C N -2 0 1
N o r m a liz e d fE P S P s lo p e (% )
G lu N 2 C
G lu N 2 D
GluN2A selective
20
40
60
80
100
TBS
60
0
20
40
T im e (m in )
Ife n p ro d il
60
80
100
T im e (m in s )
SGE-201 enhances synaptic plasticity in aged rats (Paul et al, 2013)
1 .0 0
1 .0 0
0 .7 5
0 .7 5
0 .5 0
SGE-301 and SGE-550 demonstrate minimal
off-target activity
0 .5 0
G lu N 2 A
G lu N 2 B
0 .2 5
0 .2 5
G lu N 2 C
G lu N 2 D
0 .0 0
S G E -3 0 1
150
10
0 .0 1
0 .1
1
10
GluN2C/D selective PAM
C IQ
4 .0 0
s ig m a
1 .0 0
3 .0 0
0 .7 5
2 .0 0
0 .5 0
1 .0 0
0 .2 5
0 .0 0
0 .0 0
100
0 .1
1
10
100
G lu N 2 B *
0 .1
1
100
C o n c e n t r a t io n (  M )
C o n c e n t r a t io n (  M )
50
10
T a rg e t
S G E -2 0 1
1
Q N Z -4 6
N o r m a liz e d C u r r e n t
Cells expressing hGluN1/hGluN2a
0 .1
GluN2C/D selective
SGE-201 and SGE-301 potentiate NMDA currents in
heterologous mammalian cells
% P o t e n t ia t io n
0 .7 5
[ G lu t a m a t e ] (  M )
0 .0 1
+ SGE-301
G lu N 2 B
0 .0 0 1
0 .0 0
200
G lu N 2 A
0 .0 0
N o r m a liz e d C u r r e n t
Paul et al, J. Neurosci 33(44):17290-300. 2013
180
1 .0 0
0.1μA
• We recently reported (Paul et al, 2013) that the endogenous
neuroactive steroid, 24(S)-hydroxycholesterol (24(S)-HC)
directly modulates the NMDA receptor and positively impacts
plasticity in the hippocampus
Reference:
P 6 0~90 day
Glutamate (μM)
• In particular, given the role of NMDA receptors in mnemonic
processes, positive modulators of NMDA receptors are of
interest for their potential to alleviate cognitive deficits
• We have identified a series of novel neuroactive steroids that
act as PAMs of the NMDA receptor
SGE-201 enhances hippocampal plasticity in aged rats
GluN1/GluN2A
N o r m a liz e d C u r r e n t
Overview
H1
0
10
100
1000
C o n c e n t r a t io n ( n M )
SAGE NMDA-R PAMs exhibit diverse
subunit selectivity profiles
SAGE compounds exhibit a range of activities
S G E -3 0 1
2 4 (S )-H C
S G E -2 0 1
S G E -5 5 0
Activity at 1μM in cells expressing hGluN1/hGluN2a
600
400
S G E -3 0 1
2 .5
2 .0
1 .5
1 .0
1 .0
100
0
Com pound
www.sagerx.com/posters/poster1.pdf
0 .1
1
10
100
0 .0 1
2 .5
2 .0
2 .0
1 .5
1 .5
1 .0
1 .0
0 .1
1
C o n c e n t r a t io n (  M )
0 .1
1
10
100
10
100
S G E -5 5 0
2 .5
0 .0 1
50
75
100
Conclusions
S G E -3 0 1
S G E -5 5 0
25
2 .0
1 .5
S G E -2 0 1
2 4 (S )-H C
0
% In h ib itio n
G lu N 2 D
0 .0 1
200
2 .5
G lu N 2 B
G lu N 2 C
300
N o r m a liz e d C u r r e n t
% P o t e n t ia t io n
500
N o r m a liz e d C u r r e n t
G lu N 2 A
10
100
0 .0 1
0 .1
1
C o n c e n t r a t io n (  M )
• We have developed a novel series of positive allosteric
modulators of the NMDA-R based on the endogenous
neuroactive steroid, 24(S)-HC
• These compounds show activity across a diverse range of
native and heterologously expressed NMDA-R
• These compounds may ameliorate age related deficits in
hippocampal plasticity
• As such, these series of NMDA-R PAMs exhibited by SGE301 and SGE-550 represent a novel therapeutic class of
molecules which may have utility in CNS disorders