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Properties of Memantine and Mechanism of Action

Properties of Memantine and Mechanism of Action. Structural Formula of Memantine. 1-amino-3,5-dimethyl-adamantane. NH 3 +. CH 3. H 3 C. 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 1-amino-3,5-dimethyl-adamantane NH3+ CH3 H3C

  3. Memantine is a NMDA Receptor Channel Antagonist [³H]-MK-801 binding to homogenates of postmortem human cortex 100 80 60 40 20 0  MemantineKi = 0.54 ± 0.04 µM  MK-801Ki = 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. Memantine Mg 2+ MK-801 Kinetics of NMDA-Receptor Blockade Intermediate between Mg2+ and MK-801 Mg 2+ shows very fast blockade of NMDA receptors Memantineshows fast blockade of NMDA receptors (+)MK-801shows very slow blockade of NMDA receptors and also fast unblockade and also relatively fast unblockade and also slow 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 Pathological condition Physiological synaptic neurotransmission (- 70mV) (- 50mV) (- 20mV) Magnesium Memantine MK-801, PCP Parsons et al., Neuropharmacolgy 1999 (mod. from Kornhuber)

  7. Pathological activation of NMDA receptors Neuroprotection by memantine Memantine improves plastic processes Ca2+ rest M rest learning Ca2+ Ca2+ M signal detected Glutamate Magnesium Memantine M signal noise noise noise Memantine in Neurodegenerative Dementia Danysz et al., Neurotox Res 2000

  8. 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 Memantine Treatment Can not Be Replaced by Magnesium

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