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Mode of Action of Perampanel : a selective non-competitive AMPA receptor antagonist

Mode of Action of Perampanel : a selective non-competitive AMPA receptor antagonist. Information prepared by Eisai Europe Ltd. Contents. Mode of Action (MOA) of existing anti-epileptic drugs (AEDs) Glutamate mediated Post Synaptic Excitation

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Mode of Action of Perampanel : a selective non-competitive AMPA receptor antagonist

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  1. Mode of Action of Perampanel:a selective non-competitiveAMPA receptor antagonist Information prepared by Eisai Europe Ltd

  2. 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

  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: • Pre-synaptic excitability and transmitter release • GABA inhibitory systems • Post-synaptic glutamate receptors

  4. 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: • Pre-synaptic excitability and transmitter release • GABA inhibitory systems • Post-synaptic glutamate receptors

  5. 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 Post-synaptic neuron Redrawn and adapted from: Rogawski MA, Löscher W. Nat Rev Neurosci2004;5:553–564; Rogawski MA. Epilepsy Currents 2011;11:56–63.

  6. 2. GABA inhibitory systems 2. GABA inhibitory systems Pre-synaptic neuron GABAA receptor GABA transaminase GABA transporter Inhibitory interneuron Post-synaptic neuron Redrawn and adapted from : Rogawski MA, Löscher W. Nat Rev Neurosci2004;5:553–564; Rogawski MA. Epilepsy Currents 2011;11:56–63.

  7. 3. Post-synaptic excitability 3. Post-synaptic excitability Not targeted selectively by any approved AEDs prior to perampanel Pre-synaptic neuron 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 Post-synaptic neuron Redrawn and adapted from: Rogawski MA, Löscher W. Nat Rev Neurosci2004;5:553–564; Rogawski MA. Epilepsy Currents 2011;11:56–63.

  8. Glutamate mediated Post-synaptic excitability

  9. 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 • 1Rogawski MA. Epilepsy Currents 2011;11:56–63; 2Meldrum BS. J Nutr2000;130:1007S–1015S; 3Meldrum BS, Rogawski MA. Neurotherapeutics 2007;4:18–61. Kainate receptor NMDA receptor AMPA receptor

  10. 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 • Rogawski MA. Epilepsy Currents; 2011;11:56–63. Action potentials EPSP

  11. 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 • 1Rogawski MA. Epilepsy Currents; 2011;11:56–63; 2Meldrum BS. J Nutr2000;130:1007S–1015S; 3Meldrum BS, Rogawski MA. Neurotherapeutics 2007;4:18–61. EPSP Fast Slow

  12. 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 • 1Acharya JN. Curr Sci2002;82:679–688; 2Chapman AG. J Nutr 2000;130:1043S–1045S. EPSP PDS Initial component mediated by AMPA receptors Later component mediated by NMDA receptors

  13. 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.

  14. Glutamate and the AMPA receptor play an important role in seizure activity • 1During MJ, Spencer DD. Lancet 1993;341:1607–1610; 2Meldrum BS, Rogawski MA. Neurotherapeutics 2007;4:18–61; 3Meldrum BS. J Nutr2000;130:1007S–1015S; 4Rogawski MA, Donevan SD. Adv Neurol 1999;79:947–63; 5Acharya JN. Curr Sci2002;82:679–688; 6Chapman AG. J Nutr 2000;130:1043S–1045S. • 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

  15. AMPA receptor structure • 1Wilcox KS et al. In: Epilepsy: a comprehensive textbook. 2008; 2Clements JD et al. J Neurosci 1998;18:119–121. 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 The receptor’s ion channel allows influx of Na+ ions (and sometimes Ca2+ ions) into the neuron

  16. Glutamate opens the AMPA receptor to allow Na+ influx Normal situation • Wilcox KS et al. In: Epilepsy: a comprehensive textbook. 2008. 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

  17. Competitive antagonists may be displaced by high levels of glutamate In the presence of a competitive antagonist • Rang HP et al. In: Pharmacology. 1995. 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 Competitiveantagonist

  18. Non-competitive antagonists should maintain activity even when glutamate levels are high In the presence of perampanel1 • 1Hanada T et al. Epilepsia2011;52:1331–1340; 2Kenakin T. Molecular Interventions 2004;4:222–229. 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 Perampanel

  19. AMPA receptor antagonism and seizure activity AMPA receptors: • Important role in seizure initiation and spread • Important and promising target for epilepsy therapy • 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

  20. Perampanel is selective for AMPA receptors • a300-times higher concentration required to achieve a smaller inhibitory effect • 1Hanada T et al.Epilepsia2011;52(7):1331–1340; 2Tokuhara N et al. Poster presented at AAN 2008. 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

  21. Perampanel is a non-competitive antagonist • Hanada T et al. Epilepsia 2011;52(7):1331–1340. Radiolabelled binding studies demonstrate perampanel binds at a non-competitive site • In 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

  22. Perampanel is a selective, non-competitive, AMPA receptor antagonist • 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. What does this mean?

  23. Perampanel is a selective, non-competitive, AMPA receptor antagonist • 1Hanada 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. What are the theoretical implications?

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