MOA slides - Epilepsy treatment

Report
Mode of Action of Perampanel:
a selective non-competitive
AMPA receptor antagonist
Information prepared by Eisai Europe Ltd
1
Contents
• Mode of Action (MOA) of existing anti-epileptic drugs (AEDs)
• Glutamate mediated Post Synaptic Excitation
• MOA of Perampanel, a selective, non-competitive AMPA receptor
antagonist
•
AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid
2
Understanding key transmitter systems is important
in understanding seizures and AED actions
• The CNS uses a large number of ion channels, neurotransmitters, and
receptors to communicate
• Several of these systems are important in understanding epilepsy
– The biological mechanisms underlying seizure activity
– The mechanism of action of antiepileptic drugs (AEDs)
• The following slides provide information on some of these key ion
channels and neurotransmitter systems, arranged in 3 conceptual
groups:
1. Pre-synaptic excitability and transmitter release
2. GABA inhibitory systems
3. Post-synaptic glutamate receptors
3
Understanding key transmitter systems is important
in understanding seizures and AED actions
• The CNS uses a large number of ion channels, neurotransmitters, and
receptors to communicate
• Several of these systems are important in understanding epilepsy
– The biological mechanisms underlying seizure activity
– The mechanism of action of antiepileptic drugs (AEDs)
• The following slides provide information on some of these key ion
channels and neurotransmitter systems, arranged in 3 conceptual
groups:
1. Pre-synaptic excitability and transmitter release
2. GABA inhibitory systems
3. Post-synaptic glutamate receptors
4
1. Pre-synaptic excitability and neurotransmitter
release
1. Pre-synaptic excitability and transmitter release
Pre-synaptic
neuron
Voltage-gated Na+ channel
Voltage-gated K+ channel
Voltage-gated Ca2+ channel
Inhibitory interneuron
Redrawn and adapted from: Rogawski MA, Löscher W. Nat Rev Neurosci 2004;5:553–564;
Rogawski MA. Epilepsy Currents 2011;11:56–63.
Post-synaptic neuron
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2. GABA inhibitory systems
2. GABA inhibitory systems
Pre-synaptic
neuron
GABAA receptor
GABA transaminase
GABA transporter
Inhibitory interneuron
Redrawn and adapted from : Rogawski MA, Löscher W. Nat Rev Neurosci 2004;5:553–564;
Rogawski MA. Epilepsy Currents 2011;11:56–63.
Post-synaptic neuron
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3. Post-synaptic excitability
3. Post-synaptic
excitability
Pre-synaptic
neuron
Not targeted selectively by any
approved AEDs prior to
perampanel
Felbamate has weak affinity for NMDA
receptors and topiramate binds both AMPA
and kainate receptors...
...but the primary MOA of
these AEDs is inhibition of voltage-gated
Na+ channels
AMPA receptor
Glutamate
NMDA receptor
Inhibitory interneuron
Redrawn and adapted from: Rogawski MA, Löscher W. Nat Rev Neurosci 2004;5:553–564;
Rogawski MA. Epilepsy Currents 2011;11:56–63.
Post-synaptic neuron
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Glutamate mediated Post-synaptic excitability
8
Glutamate mediates most fast excitatory
neurotransmission in the CNS
• Glutamate is the principal excitatory neurotransmitter in the CNS1
– Effects mediated via ionotropic receptors (ion channels) and metabotropic
receptors1,2
• Ionotropic receptors mediate glutamate’s fast excitatory
neurotransmission at synapses2,3
– Three types, all activated by glutamate but named after the synthetic agonists
used to characterise the receptors:
AMPA: -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
NMDA: N-methyl-D-aspartate
Kainate: Kainic acid
AMPA receptor
Kainate receptor
NMDA receptor
1Rogawski
MA. Epilepsy Currents 2011;11:56–63; 2Meldrum BS. J Nutr 2000;130:1007S–1015S; 3Meldrum BS, Rogawski
MA. Neurotherapeutics 2007;4:18–61.
9
AMPA receptors mediate glutamate fast signalling
• AMPA receptors are the most abundant ionotropic glutamate receptors in
the mammalian brain
• They are localised at excitatory synapses, post-synaptically
• AMPA receptors mediate the fast response to glutamate
– Generate the fast component of the excitatory post synaptic potential (EPSP)
– If sufficient EPSPs result, these summate and result in firing of an action potential
Action potentials
EPSP
Rogawski MA. Epilepsy Currents; 2011;11:56–63.
10
Glutamate mediates most fast excitatory
neurotransmission in the CNS
• AMPA is the main receptor mediating rapid effects of glutamate1
– Underlies fast component of EPSP1,2
• NMDA receptor does not normally contribute to fast
neurotransmission1,2
– Underlies slow component of the EPSP1,2
– Involved in plasticity e.g. learning and memory1,3
EPSP
Fast
Slow
1Rogawski
MA. Epilepsy Currents; 2011;11:56–63; 2Meldrum BS. J Nutr 2000;130:1007S–1015S; 3Meldrum BS, Rogawski
MA. Neurotherapeutics 2007;4:18–61.
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AMPA receptors may trigger seizure activity via the
PDS (Paroxysmal Depolarising Shift)
• AMPA receptors drive EPSPs at individual
synapses and across networks
• Synchronised EPSPs across neuronal networks
are thought to drive the PDS1,2
• The AMPA receptor is thought to mediate the initial
component of the PDS
Initial component
mediated by
AMPA receptors
EPSP
PDS
Later component mediated
by NMDA receptors
1Acharya
JN. Curr Sci 2002;82:679–688; 2Chapman AG. J Nutr 2000;130:1043S–1045S.
12
Neuronal hyperexcitability results, somehow,
in seizures
• Individual neurons within an
area may be hyperexcitable1
• These neurons occasionally
have sudden (paroxysmal),
synchronous depolarisations,
and fire bursts of action
potential bursts1
– Paroxysmal depolarisation
shift (PDS)2
PDS
1Dichter
MA. In: Epilepsy. A comprehensive textbook. 2008; 2Rang HP et al. In: Pharmacology. 1995.
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Glutamate and the AMPA receptor play an important
role in seizure activity
• Glutamate and the AMPA receptor are important in seizure activity1–4
• Glutamate is implicated in acute and chronic neurodegeneration
• How do we know glutamate is important in seizures?
– Glutamate levels increase before and during seizures in humans1
• Suggests that elevated glutamate levels can trigger and maintain seizures
– AMPA receptor agonists initiate seizures in animal models3
– AMPA receptor antagonists have anti-seizure activity in animal models3
• Suggests AMPA receptors are involved in seizure initiation and spread2–4
• How are AMPA receptors involved in seizures?
– AMPA receptors are known to drive EPSPs at excitatory synapses (normal
neuronal activity)
– It is thought that AMPA receptors are involved in the PDS (Paroxysmal
Depolarising Shift)5,6
1During
MJ, Spencer DD. Lancet 1993;341:1607–1610; 2Meldrum BS, Rogawski MA. Neurotherapeutics 2007;4:18–61;
3Meldrum BS. J Nutr 2000;130:1007S–1015S; 4Rogawski MA, Donevan SD. Adv Neurol 1999;79:947–63; 5Acharya JN. Curr
Sci 2002;82:679–688; 6Chapman AG. J Nutr 2000;130:1043S–1045S.
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AMPA receptor structure
AMPA receptor
(closed, inactive state)
AMPA receptor
(open, active state)
Glutamate-binding sites
(also ligand-binding sites or domains)
Na+ ions
Glutamate
Non-competitive
binding sites
1Wilcox
KS et al. In: Epilepsy: a comprehensive textbook. 2008;
JD et al. J Neurosci 1998;18:119–121.
2Clements
The receptor’s ion channel allows
influx of Na+ ions (and sometimes
Ca2+ ions) into the neuron
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Glutamate opens the AMPA receptor to allow
Na+ influx
Normal situation
1. Glutamate binds and
activates the receptor
2. Na+ enters through the
open channel
3. Channel returns to
closed state when
glutamate dissociates
Na+ ions
Glutamate
Wilcox KS et al. In: Epilepsy: a comprehensive textbook. 2008.
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Competitive antagonists may be displaced by high
levels of glutamate
In the presence of a competitive antagonist
1. Glutamate cannot bind
so cannot activate the
receptor
BUT when glutamate levels are high...
2. Glutamate displaces the
antagonist...
3. ...binds to the receptor
and activates it, opening
the channel and allowing
Na+ influx
Na+ ions
Glutamate
Rang HP et al. In: Pharmacology. 1995.
Competitive
antagonist
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Non-competitive antagonists should maintain activity
even when glutamate levels are high
In the presence of perampanel1
1. Glutamate binds but
cannot activate the
receptor1
AND when glutamate levels are high...
2. ...non-competitive
antagonist is not
displaced by glutamate2
3. Receptor antagonism
is maintained and the
channel remains
closed
Na+ ions
Glutamate
1Hanada
T et al. Epilepsia 2011;52:1331–1340; 2Kenakin T. Molecular Interventions 2004;4:222–229.
Perampanel
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AMPA receptor antagonism and seizure activity
AMPA receptors:
• Important role in seizure initiation and spread
• Important and promising target for epilepsy
therapy
AMPA receptor antagonists:
• Anti-seizure activity in a broad
range of animal models
Perampanel:
• A non-competitive AMPA receptor
antagonist
• Studied in Phase III clinical trials in patients
with refractory partial-onset seizures
Rogawski MA. Epilepsy Currents 2011;11:56–63.
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Perampanel is selective for AMPA receptors
In ligand-binding studies1,2
• Perampanel has minimal affinity for receptors other than the AMPA
receptor
In receptor function studies1
• Perampanel inhibits function of AMPA receptors at concentrations that
have no effect on NMDA receptor function
Effect on AMPA receptor function
50% inhibition at 93 nMa
a300-times
1Hanada
Effect on NMDA receptor function
18% inhibition at 30 μMa
higher concentration required to achieve a smaller inhibitory effect
T et al. Epilepsia 2011;52(7):1331–1340; 2Tokuhara N et al. Poster presented at AAN 2008.
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Perampanel is a non-competitive antagonist
Radiolabelled binding studies demonstrate perampanel binds at a noncompetitive site
•
In these studies, perampanel was radioactively labelled, and its binding to
neuronal membranes in vitro was measured
•
Radiolabelled perampanel binds with high affinity
–
•
Adding AMPA or glutamate does not reduce binding of radio-labelled perampanel
–
•
This shows that perampanel binds to a specific target site in the brain
This shows that perampanel does NOT bind to the glutamate-binding site of the AMPA receptor; if it
did, glutamate and AMPA would displace its binding
Adding known non-competitive AMPA receptor antagonists does reduce binding
of radio-labelled perampanel
–
This shows that perampanel DOES bind to a non-competitive site
Hanada T et al. Epilepsia 2011;52(7):1331–1340.
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Perampanel is a selective, non-competitive,
AMPA receptor antagonist
What does this mean?
Explanation1–3
AMPA receptor antagonist1
• Reduces the ability of glutamate (or any other AMPA
receptor agonist) to activate the AMPA receptor
• Selectively binds to AMPA receptors
Selective1
• Doesn’t have significant affinity for other glutamate
receptors or other receptors or transporters
• Binds to the AMPA receptor at a non-competitive site
Non-competitive1
–
Does not DIRECTLY block glutamate from binding to the
receptor at the glutamate-binding site
–
Does INDIRECTLY (or non-competitively) inhibit the
ability of glutamate to activate the receptor, by binding to
the AMPA receptor at a non-competitive site
1Hanada
T et al. Epilepsia 2011;52(7):1331–1340; 2Rang HP et al. In: Pharmacology. 1995; 3Kenakin T. Molecular
Interventions 2004;4:222–229.
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Perampanel is a selective, non-competitive,
AMPA receptor antagonist
What are the theoretical implications?
Implications1–4
AMPA receptor antagonist1
Selective1
• Reduces activation of AMPA receptors by glutamate,
reducing excitability of neurons expressing these
receptors
• Perampanel is unlikely to have effects on non-AMPA
glutamate receptors
– low potential for phencyclidine-likea effects as no
significant NMDA receptor binding
• Unlikely to have effects on other receptors or
transporters
• Activity of a non-competitive antagonist is maintained
even when levels of the agonist (e.g. glutamate) are high
Non-competitive1
• In contrast, a competitive antagonist is displaced (outcompeted) when agonist concentrations are high, allowing
glutamate to bind and activate the receptor
also known as ‘angel dust’ or PCP
T et al. Epilepsia 2011;52(7):1331–1340; 2Rogawski MA. Epilepsy Currents 2011;11:56–63; 3Kenakin T. In: A
Pharmacology Primer. 2006; 4Rang HP et al. In: Pharmacology. 1995.
aPhencyclidine
1Hanada
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