Memantine Properties and MOA 2006

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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
(³H)-MK-801 binding to homogenates of postmortem human cortex

                                    100
Specific (3H)-MK-801 Binding (%)




                                                                             Memantine
                                    80                                        Ki = 0.54 ± 0.04 µM
                                                                             MK-801
                                    60                                        Ki = 0.0012 ± 0.00015 µM


                                    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
Mg2+ showsshowsfast blockade of NMDA NMDA receptors
Memantine very fast slow blockade of receptors
(+)MK-801 shows very blockade of NMDA receptors
         slow unblockade
         relatively fast unblockade
and also 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
                              Memantine
Control Response (%)




                        80    Mg2+
                              MK-801
                        60

                        40

                        20

                        0
                                          resting      pathological     physiological
                                         condition      activation      synaptic transmisson
                                      Increasing membrane potential

                                                         Parsons et al., Neuropharmacology 1993
              Properties of Memantine
               Resting         Pathological         Physiological synaptic
              Condition         Condition            Neurotransmission
              (- 70mV)          (- 50mV)                  (- 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:       • Glutamate transmits signal via        Postsynaptic:
Neuronal signal      the NMDA receptor                     Detected signal
                   • Recycling of glutamate in glia cell
         AXURA: Mechanism of Action

Alzheimer’s Disease


                           ß-Amyloid




                            GLUTAMATE




Presynaptic:          • ß-Amyloid inhibits glutamate    Postsynaptic:
Neuronal signal         recycling                       Inhibited signal
                      • Excess glutamate masks signal   detection
                        transmission
         AXURA: Mechanism of Action

AXURA Treatment


                       ß-Amyloid




                        GLUTAMATE




Presynaptic:      • AXURA blocks effect of excess   Postsynaptic:
Neuronal signal     glutamate                       Stabilized signal
                  • Restoration of physiological    detection
                    signal transmission
      Memantine: Mechanism of Action

Normal Situation




                         GLUTAMATE




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

Alzheimer’s Disease


                           ß-Amyloid




                            GLUTAMATE




Presynaptic:          • ß-Amyloid inhibits glutamate    Postsynaptic:
Neuronal signal         recycling                       Inhibited signal
                      • Excess glutamate masks signal   detection
                        transmission
      Memantine: Mechanism of Action

Memantine Treatment


                        ß-Amyloid




                                         Memantine




                         GLUTAMATE




Presynaptic:      • Memantine blocks effect          Postsynaptic:
Neuronal signal     excess glutamate                 Stabilized signal
                  • Restoration of physiological     detection
                    signal transmission
         AXURA: Mechanism of Action

Normal Situation




                         GLUTAMATE




Presynaptic:       Glutamate as signal transmitter   Postsynaptic:
Neuronal signal                                      Detected signal
         AXURA: Mechanism of Action

Alzheimer’s Disease




                            GLUTAMATE




Presynaptic:          Excess glutamate masks signal   Postsynaptic:
Neuronal signal       transmission                    Inhibited signal
                                                      detection
         AXURA: Mechanism of Action

AXURA Treatment




                        GLUTAMATE




Presynaptic:      • AXURA blocks effect of excess   Postsynaptic:
Neuronal signal     glutamate                       Stabilized signal
                  • Restoration of physiological    detection
                    signal transmission
      Memantine: Mechanism of Action

Normal Situation




                         GLUTAMATE




Presynaptic:       Glutamate as signal transmitter   Postsynaptic:
Neuronal signal                                      Detected signal
      Memantine: Mechanism of Action

Alzheimer’s Disease




                            GLUTAMATE




Presynaptic:          Excess glutamate masks signal   Postsynaptic:
Neuronal signal       transmission                    Inhibited signal
                                                      detection
      Memantine: Mechanism of Action

Memantine Treatment




                                            Memantine




                            GLUTAMATE




Presynaptic:          • Memantine blocks effect of      Postsynaptic:
Neuronal signal         excess glutamate                Stabilized signal
                      • Restoration of physiological    detection
                        signal transmission
      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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