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Properties of Memantine and Mechanism of Action

Properties of Memantine and Mechanism of Action. Structural Formula of Memantine. NH 3 +. CH 3. H 3 C. 1-amino-3,5-dimethyl-adamantane. Memantine is a NMDA Receptor Channel Antagonist. (³H)-MK-801 binding to homogenates of postmortem human cortex. 100 80 60 40 20 0.

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Properties of Memantine and Mechanism of Action

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  1. Properties of Memantineand Mechanism of Action

  2. Structural Formula of Memantine NH3+ CH3 H3C 1-amino-3,5-dimethyl-adamantane

  3. Memantine is a NMDA Receptor Channel Antagonist (³H)-MK-801 binding to homogenates of postmortem human cortex 100 80 60 40 20 0 Memantine Ki = 0.54 ± 0.04 µM MK-801 Ki = 0.0012 ± 0.00015 µM Specific (3H)-MK-801 Binding (%) 0.01 0.1 1 10 100 Concentration (µM) Kornhuber et al., Eur J Pharmacol 1989

  4. Kinetics of NMDA-Receptor Blockade Intermediate between Mg2+ and MK-801 Memantine Mg2+ MK-801 Mg2+ shows very fast blockade of NMDA receptors (+)MK-801shows very slow blockade of NMDA receptors Memantineshows fast blockade of NMDA receptors and also fast unblockade and also slow unblockade and also relatively fast unblockade Peaks represent responses to application of NMDA time Parsons et al., Neuropharmacology 1993

  5. Moderate Voltage-Dependency of Memantine The voltage-dependency of memantine is intermediate between that of Mg2+ and MK-801 100 80 60 40 20 0 Memantine Mg2+ MK-801 Control Response (%) resting condition pathological activation physiological synaptic transmisson Increasing membrane potential Parsons et al., Neuropharmacology 1993

  6. Properties of Memantine Ca2+ Ca2+ Ca2+ Resting Condition (- 70mV) Pathological Condition (- 50mV) Physiological synaptic Neurotransmission (- 20mV) Magnesium Memantine MK-801, PCP Parsons et al., Neuropharmacolgy 1999 (mod. from Kornhuber)

  7. AXURA: Mechanism of Action GLUTAMATE Postsynaptic: Detected signal Presynaptic: Neuronal signal • Glutamate transmits signal via • the NMDA receptor Normal Situation • Recycling of glutamate in glia cell

  8. AXURA: Mechanism of Action ß-Amyloid GLUTAMATE Postsynaptic: Inhibited signal detection Presynaptic: Neuronal signal • ß-Amyloid inhibits glutamate recycling Alzheimer’s Disease • Excess glutamate masks signal • transmission

  9. AXURA: Mechanism of Action ß-Amyloid GLUTAMATE Postsynaptic: Stabilized signal detection Presynaptic: Neuronal signal • AXURA blocks effect of excess glutamate AXURA Treatment • Restoration of physiological signal transmission

  10. Memantine: Mechanism of Action GLUTAMATE Postsynaptic: Detected signal Presynaptic: Neuronal signal • Glutamate transmits signal via • the NMDA receptor Normal Situation • Recycling of glutamate in glia cell

  11. Memantine: Mechanism of Action ß-Amyloid GLUTAMATE Postsynaptic: Inhibited signal detection Presynaptic: Neuronal signal • ß-Amyloid inhibits glutamate recycling Alzheimer’s Disease • Excess glutamate masks signal • transmission

  12. Memantine: Mechanism of Action ß-Amyloid Memantine GLUTAMATE Postsynaptic: Stabilized signal detection • Memantine blocks effect excess glutamate Presynaptic: Neuronal signal Memantine Treatment • Restoration of physiological signal transmission

  13. AXURA: Mechanism of Action GLUTAMATE Postsynaptic: Detected signal Presynaptic: Neuronal signal Glutamate as signal transmitter Normal Situation

  14. AXURA: Mechanism of Action Excess glutamate GLUTAMATE Postsynaptic: Inhibited signal detection Presynaptic: Neuronal signal Excess glutamate masks signal transmission Alzheimer’s Disease

  15. AXURA: Mechanism of Action Excess glutamate Excess glutamate GLUTAMATE Postsynaptic: Stabilized signal detection Presynaptic: Neuronal signal • AXURA blocks effect of excess glutamate AXURA Treatment • Restoration of physiological signal transmission

  16. Memantine: Mechanism of Action GLUTAMATE Postsynaptic: Detected signal Presynaptic: Neuronal signal Glutamate as signal transmitter Normal Situation

  17. Memantine: Mechanism of Action Excess glutamate GLUTAMATE Postsynaptic: Inhibited signal detection Presynaptic: Neuronal signal Excess glutamate masks signal transmission Alzheimer’s Disease

  18. Memantine: Mechanism of Action Excess glutamate Memantine GLUTAMATE Postsynaptic: Stabilized signal detection Presynaptic: Neuronal signal • Memantineblocks effect of excess glutamate Memantine Treatment Excess glutamate • Restoration of physiological signal transmission

  19. Memantine Treatment Can not Be Replaced by Magnesium Pharmacokinetic reasons: • Mg2+: poorly absorbed from GI tract (Fawcett et al., 1999) • Mg2+: hardly passes blood-brain barrier (Hallak, 1998) • High parenteral dosages required which may lead to life-threatening adverse events due to hypermagnesemia (reviewed by Fung et al., 1995) Pharmacodynamic reasons: • Due to higher voltage dependency Mg2+ is expected to have less capacity to block sustained background noise • Potential interaction of Mg2+ with central cholinergic system may lead to impairment of cholinergic neurotransmission (Fung et al., 1995; Ladner and Lee, 1999) • Worsening of cholinergic deficit in AD patients

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