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Properties of Memantine and Mechanism of Action Structural Formula of Memantine 1-amino-3,5-dimethyl-adamantane NH3+ CH3 H3C Memantine is a NMDA Receptor Channel Antagonist Specific (3H)-MK-801 Binding (%) (³H)-MK-801 binding to homogenates of postmortem human cortex 100 Memantine Ki = 0.54 ± 0.04 µM 80 MK-801 Ki = 0.0012 ± 0.00015 µM 60 40 20 0 0.01 0.1 1 10 100 Concentration (µM) Kornhuber et al., Eur J Pharmacol 1989 Kinetics of NMDA-Receptor Blockade Intermediate between Mg2+ and MK-801 2+ showsshows Memantine Mg (+)MK-801 shows very fast very fastblockade blockade slow blockade ofofNMDA NMDA of NMDA receptors receptors receptors and also relatively fast unblockade slow unblockade fast unblockade Mg2+ Memantine MK-801 Peaks represent responses to application of NMDA time Parsons et al., Neuropharmacology 1993 Moderate Voltage-Dependency of Memantine The voltage-dependency of memantine is intermediate between that of Mg2+ and MK-801 100 Control Response (%) Memantine 80 Mg2+ MK-801 60 40 20 0 resting condition pathological activation physiological synaptic transmisson Increasing membrane potential Parsons et al., Neuropharmacology 1993 Properties of Memantine Resting Condition (- 70mV) Pathological Condition (- 50mV) Physiological synaptic Neurotransmission (- 20mV) Ca2+ Ca2+ Magnesium Ca2+ Memantine MK-801, PCP Parsons et al., Neuropharmacolgy 1999 (mod. from Kornhuber) AXURA: Mechanism of Action Normal Situation GLUTAMATE Presynaptic: Neuronal signal • Glutamate transmits signal via the NMDA receptor • Recycling of glutamate in glia cell Postsynaptic: Detected signal AXURA: Mechanism of Action Alzheimer’s Disease ß-Amyloid GLUTAMATE Presynaptic: Neuronal signal • ß-Amyloid inhibits glutamate recycling • Excess glutamate masks signal transmission Postsynaptic: Inhibited signal detection AXURA: Mechanism of Action AXURA Treatment ß-Amyloid GLUTAMATE Presynaptic: Neuronal signal • AXURA blocks effect of excess glutamate • Restoration of physiological signal transmission Postsynaptic: Stabilized signal detection Memantine: Mechanism of Action Normal Situation GLUTAMATE Presynaptic: Neuronal signal • Glutamate transmits signal via the NMDA receptor • Recycling of glutamate in glia cell Postsynaptic: Detected signal Memantine: Mechanism of Action Alzheimer’s Disease ß-Amyloid GLUTAMATE Presynaptic: Neuronal signal • ß-Amyloid inhibits glutamate recycling • Excess glutamate masks signal transmission Postsynaptic: Inhibited signal detection Memantine: Mechanism of Action Memantine Treatment ß-Amyloid Memantine GLUTAMATE Presynaptic: Neuronal signal • Memantine blocks effect excess glutamate • Restoration of physiological signal transmission Postsynaptic: Stabilized signal detection AXURA: Mechanism of Action Normal Situation GLUTAMATE Presynaptic: Neuronal signal Glutamate as signal transmitter Postsynaptic: Detected signal AXURA: Mechanism of Action Alzheimer’s Disease GLUTAMATE Presynaptic: Neuronal signal Excess glutamate masks signal transmission Postsynaptic: Inhibited signal detection AXURA: Mechanism of Action AXURA Treatment GLUTAMATE Presynaptic: Neuronal signal • AXURA blocks effect of excess glutamate • Restoration of physiological signal transmission Postsynaptic: Stabilized signal detection Memantine: Mechanism of Action Normal Situation GLUTAMATE Presynaptic: Neuronal signal Glutamate as signal transmitter Postsynaptic: Detected signal Memantine: Mechanism of Action Alzheimer’s Disease GLUTAMATE Presynaptic: Neuronal signal Excess glutamate masks signal transmission Postsynaptic: Inhibited signal detection Memantine: Mechanism of Action Memantine Treatment Memantine GLUTAMATE Presynaptic: Neuronal signal • Memantine blocks effect of excess glutamate • Restoration of physiological signal transmission Postsynaptic: Stabilized signal detection 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