a selective noncompetitive AMPA receptor antagonist Information prepared by Eisai Europe Ltd 1 Mode of Action MOA of existing antiepileptic drugs AEDs Glutamate mediated Post Synaptic Excitation ID: 815233
Download The PPT/PDF document "Mode of Action of Perampanel" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Mode of Action of Perampanel:a selective non-competitiveAMPA receptor antagonist
Information prepared by Eisai Europe Ltd
1
Slide2Mode of Action (MOA) of existing anti-epileptic drugs (AEDs) Glutamate mediated Post Synaptic ExcitationMOA of Perampanel, a selective, non-competitive AMPA receptor antagonist
AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid
Contents
2
Slide3Understanding key transmitter systems is important in understanding seizures and AED actionsThe CNS uses a large number of ion channels, neurotransmitters, and receptors to communicateSeveral of these systems are important in understanding epilepsyThe 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:
Pre-synaptic excitability and transmitter release
GABA inhibitory systems
Post-synaptic glutamate receptors
3
Slide4Understanding key transmitter systems is important in understanding seizures and AED actionsThe CNS uses a large number of ion channels, neurotransmitters, and receptors to communicateSeveral of these systems are important in understanding epilepsyThe 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:
Pre-synaptic excitability and transmitter release
GABA inhibitory systems
Post-synaptic glutamate receptors
4
Slide55
1. Pre-synaptic excitability and neurotransmitter release
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
Pre-synaptic neuron
Inhibitory interneuron
1. Pre-synaptic excitability
and transmitter release
Voltage-gated Na
+
channel
Voltage-gated K
+
channel
Voltage-gated Ca
2+
channel
Slide66
2. GABA inhibitory systems
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
Pre-synaptic neuron
Inhibitory interneuron
2. GABA inhibitory systems
GABA
A
receptor
GABA
transaminase
GABA transporter
Slide7Felbamate 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
7
3. Post-synaptic excitability
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
Pre-synaptic neuron
Inhibitory interneuron
Not targeted selectively by any approved
AEDs prior to
perampanel
3. Post-synaptic excitability
AMPA receptor
Glutamate
NMDA receptor
Slide88 Glutamate mediated Post-synaptic excitability
Slide9Glutamate is the principal excitatory neurotransmitter in the CNS1Effects mediated via ionotropic receptors (ion channels) and metabotropic receptors1,2Ionotropic receptors mediate glutamate’s fast excitatory neurotransmission at synapses2,3Three 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
1
Rogawski MA.
Epilepsy Currents
2011;11:56–63;
2
Meldrum BS.
J
Nutr
2000;130:1007S–1015S;
3
Meldrum BS, Rogawski MA.
Neurotherapeutics 2007;4:18–61.Glutamate mediates most fast excitatory neurotransmission in the CNS9
AMPA receptor
Kainate receptor
NMDA receptor
Slide10AMPA receptors are the most abundant ionotropic glutamate receptors in the mammalian brainThey are localised at excitatory synapses, post-synapticallyAMPA receptors mediate the fast response to glutamateGenerate the fast component of the excitatory post synaptic potential (EPSP)
If sufficient EPSPs result, these summate and result in firing of an action potential
Rogawski MA.
Epilepsy Currents
; 2011;11:56–63.
AMPA receptors mediate glutamate fast signalling
10
EPSP
Action potentials
Slide11AMPA
is the main receptor mediating rapid effects of glutamate1
Underlies fast component of EPSP
1,2
NMDA
receptor does not normally contribute to fast neurotransmission1,2Underlies slow component of the EPSP
1,2
Involved in plasticity e.g. learning and memory
1,3
1
Rogawski MA.
Epilepsy Currents
; 2011;11:56–63;
2
Meldrum BS.
J
Nutr
2000;130:1007S–1015S;
3
Meldrum BS, Rogawski MA.
Neurotherapeutics
2007;4:18–61.
Glutamate mediates most fast excitatory neurotransmission in the CNS
11
Fast
Slow
EPSP
Slide12PDS
AMPA receptors drive EPSPs at individual synapses and across networks
Synchronised EPSPs across neuronal networks are thought to drive the PDS
1,2
The AMPA receptor is thought to mediate the initial component of the PDS
1
Acharya JN.
Curr
Sci
2002;82:679–688;
2
Chapman AG.
J Nutr
2000;130:1043S–1045S.
AMPA receptors may trigger seizure activity via the PDS (Paroxysmal Depolarising Shift)
12
EPSP
Initial component mediated by AMPA receptors
Later component mediated by NMDA receptors
Slide13Individual neurons within an area may be hyperexcitable
1
These neurons occasionally have sudden (paroxysmal), synchronous depolarisations, and fire bursts of action potential bursts
1
Paroxysmal depolarisation shift (PDS)
2
Neuronal hyperexcitability results, somehow,
in seizures
1
Dichter MA.
In: Epilepsy. A comprehensive textbook.
2008;
2
Rang HP
et al.
In: Pharmacology.
1995.
PDS
13
Slide14Glutamate and the AMPA receptor are important in seizure activity1–4Glutamate is implicated in acute and chronic neurodegenerationHow do we know glutamate is important in seizures?Glutamate levels increase before and during seizures in humans
1Suggests that elevated glutamate levels can trigger and maintain seizures
AMPA
receptor
agonists initiate seizures in animal models
3AMPA receptor
antagonists
have anti-seizure activity in animal models
3
Suggests AMPA receptors are involved in seizure initiation and spread
2–4
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
1
During MJ, Spencer DD.
Lancet
1993;341:1607–1610;
2
Meldrum 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.Glutamate and the AMPA receptor play an important role in seizure activity
14
Slide151Wilcox KS et al. In: Epilepsy: a comprehensive textbook. 2008; 2Clements JD et al. J Neurosci 1998;18:119–121.
AMPA receptor structure
15
Non-competitive binding sites
Glutamate-binding sites
(also ligand-binding sites or domains)
AMPA receptor
(closed, inactive state)
AMPA receptor
(open, active state)
Na
+
ions
The receptor’s ion channel allows influx of Na
+
ions (and sometimes Ca
2+
ions) into the neuron
Glutamate
Slide16Normal situation
Wilcox KS et al. In: Epilepsy: a comprehensive textbook. 2008.
Glutamate opens the AMPA receptor to allow
Na
+
influx
16
1. Glutamate binds
and activates the receptor
2. Na
+
enters
through the open channel
Na
+
ions
Glutamate
3. Channel returns to closed
state when glutamate dissociates
Slide17In the presence of a competitive antagonist
Rang HP et al. In: Pharmacology. 1995
.
Competitive antagonists may be displaced by high levels of glutamate
17
1. Glutamate cannot bind
so cannot activate the receptor
2. Glutamate displaces the antagonist...
Na
+
ions
Glutamate
Competitive
antagonist
3. ...binds to the receptor and activates it,
opening the channel and allowing Na
+
influx
BUT when glutamate levels are high...
Slide18In the presence of perampanel
1
1
Hanada T
et al.
Epilepsia
2011;
52:1331–1340;
2
Kenakin T.
Molecular Interventions
2004;4:222–229.
Non-competitive antagonists should maintain activity even when glutamate levels are high
18
1. Glutamate binds
but cannot activate the receptor
1
Na
+
ions
Glutamate
Perampanel
AND when glutamate levels are high...
2. ...non-competitive antagonist is not displaced by glutamate
2
3. Receptor antagonism is maintained and the channel remains closed
Slide19AMPA receptors:
Important role in seizure initiation and spread
Important and promising target for epilepsy therapy
AMPA receptor antagonism and seizure activity
19
Rogawski MA.
Epilepsy Currents
2011;11:56–63.
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
Slide20In ligand-binding studies1,2Perampanel has minimal affinity for receptors other than the AMPA receptorIn receptor function studies1
Perampanel inhibits function of AMPA receptors at concentrations that have no effect on NMDA receptor function
a
300-times higher concentration required to achieve a smaller inhibitory effect
1
Hanada T
et al.
Epilepsia
2011;52(7):1331–1340;
2
Tokuhara N
et al.
Poster presented at AAN 2008.
Perampanel
is selective for AMPA receptors
20
Effect on AMPA receptor function
Effect on NMDA receptor function
50% inhibition at 93
nM
a
18% inhibition at 30
μ
M
a
Slide21Radiolabelled binding studies demonstrate perampanel binds at a non-competitive siteIn these studies, perampanel was radioactively labelled, and its binding to neuronal membranes in vitro was measured
Radiolabelled perampanel binds with high affinity This shows that perampanel binds to a specific target site in the brain
Adding AMPA or glutamate does
not
reduce binding of radio-labelled perampanel
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.
Perampanel
is a non-competitive antagonist
21
Slide22What does this mean? 1Hanada T et al. Epilepsia 2011;52(7):1331–1340;
2Rang HP et al. In: Pharmacology. 1995;
3
Kenakin T.
Molecular Interventions
2004;4:222–229.Perampanel is a selective, non-competitive,
AMPA receptor antagonist
22
Explanation
1–3
AMPA receptor
antagonist
1
Reduces the ability of glutamate (or any other AMPA receptor agonist) to activate the AMPA receptor
Selective
1
Selectively binds to AMPA receptors
Doesn’t have significant affinity for other glutamate receptors or other receptors or transporters
Non-competitive
1
Binds to the AMPA receptor at a non-competitive site
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
Slide23What are the theoretical implications?1Hanada T et al. Epilepsia 2011;52(7):1331–1340;
2Rogawski MA. Epilepsy Currents 2011;11:56–63;
3
Kenakin T.
In: A Pharmacology Primer. 2006;
4Rang HP et al. In: Pharmacology. 1995.
Perampanel is a selective, non-competitive,
AMPA receptor antagonist
23
Implications
1–4
AMPA receptor
antagonist
1
Reduces activation of AMPA receptors by glutamate, reducing excitability of neurons expressing these receptors
Selective
1
Perampanel is unlikely to have effects on non-AMPA glutamate receptors
low potential for phencyclidine-
like
a
effects as no significant NMDA receptor binding
Unlikely to have effects on other receptors or transporters
Non-competitive
1
Activity of a non-competitive antagonist is
maintained
even when levels of the agonist (e.g. glutamate) are high
In contrast
, a competitive antagonist is
displaced
(out-competed)
when agonist concentrations are high
, allowing glutamate to bind and activate the receptor
a
Phencyclidine
also known as ‘angel dust’ or PCP