Properties of Memantine and Mechanism of Action
19
Properties of Memantine and Mechanism of Action
description
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. - PowerPoint PPT Presentation
Transcript of Properties of Memantine and Mechanism of Action
Properties of Memantineand Mechanism of Action
NH3+
CH3
H3C
1-amino-3,5-dimethyl-adamantane
Structural Formula of Memantine
Kornhuber et al., Eur J Pharmacol 1989
(³H)-MK-801 binding to homogenates of postmortem human cortex
Spe
cific
(3 H
)-M
K-8
01 B
indi
ng (
%)
10.01 0.1 10 100
100
80
60
40
20
0
Memantine is a NMDA Receptor Channel Antagonist
Concentration (µM)
Memantine Ki = 0.54 ± 0.04 µM
MK-801 Ki = 0.0012 ± 0.00015 µM
Kinetics of NMDA-Receptor Blockade Intermediate between Mg2+ and MK-801
Mg2+ shows very fast blockade of NMDA receptors and also fast unblockade
MK-801
(+)MK-801 shows very slow blockade of NMDA receptorsand also slow unblockadeMemantine shows fast blockade of NMDA receptors
MemantineMg2+
Peaks represent responses to
application of NMDA
time
and also relatively fast unblockade
Parsons et al., Neuropharmacology 1993
Parsons et al., Neuropharmacology 1993
Con
trol
Res
pons
e (%
)
100
80
60
40
20
0
The voltage-dependency of memantine is intermediate between that of Mg2+ and MK-801
restingcondition
pathological activation
physiological synaptic transmisson
Memantine
Mg2+
MK-801
Increasing membrane potential
Moderate Voltage-Dependency of Memantine
Memantine
MK-801, PCP
Magnesium
Resting Condition(- 70mV)
PathologicalCondition(- 50mV)
Physiological synapticNeurotransmission
(- 20mV)
Parsons et al., Neuropharmacolgy 1999 (mod. from Kornhuber)
Ca2+ Ca2+
Ca2+
Properties of Memantine
Normal Situation
AXURA: Mechanism of Action
Presynaptic:Neuronal signal
• Recycling of glutamate in glia cell
Postsynaptic:Detected signal
GLUTAMATE
• Glutamate transmits signal via the NMDA receptor
Alzheimer’s Disease
AXURA: Mechanism of Action
GLUTAMATE
Presynaptic:Neuronal signal
Postsynaptic:Inhibited signal detection• Excess glutamate masks signal
transmission
ß-Amyloid
• ß-Amyloid inhibits glutamate recycling
AXURA Treatment
AXURA: Mechanism of Action
GLUTAMATE
Presynaptic:Neuronal signal
• Restoration of physiological signal transmission
Postsynaptic:Stabilized signal detection
ß-Amyloid
• AXURA blocks effect of excess glutamate
Normal Situation
Memantine: Mechanism of Action
Presynaptic:Neuronal signal
• Recycling of glutamate in glia cell
Postsynaptic:Detected signal
GLUTAMATE
• Glutamate transmits signal via the NMDA receptor
Alzheimer’s Disease
Memantine: Mechanism of Action
GLUTAMATE
Presynaptic:Neuronal signal
Postsynaptic:Inhibited signal detection• Excess glutamate masks signal
transmission
ß-Amyloid
• ß-Amyloid inhibits glutamate recycling
Memantine Treatment
Memantine: Mechanism of Action
GLUTAMATE
Presynaptic:Neuronal signal
• Restoration of physiological signal transmission
Postsynaptic:Stabilized signal detection
ß-Amyloid
• Memantine blocks effect excess glutamate
Memantine
Normal Situation
AXURA: Mechanism of Action
GLUTAMATE
Glutamate as signal transmitter Postsynaptic:Detected signal
Presynaptic:Neuronal signal
Alzheimer’s Disease
AXURA: Mechanism of Action
GLUTAMATE
Excess glutamate masks signaltransmission
Excess glutamate
Postsynaptic:Inhibited signal detection
Presynaptic:Neuronal signal
AXURA Treatment
AXURA: Mechanism of Action
Postsynaptic:Stabilized signaldetection
Presynaptic:Neuronal signal
Excess glutamate
Excess glutamate
GLUTAMATE
• AXURA blocks effect of excess glutamate
• Restoration of physiological signal transmission
Normal Situation
Memantine: Mechanism of Action
GLUTAMATE
Glutamate as signal transmitter Postsynaptic:Detected signal
Presynaptic:Neuronal signal
Alzheimer’s Disease
Memantine: Mechanism of Action
GLUTAMATE
Excess glutamate masks signaltransmission
Excess glutamate
Postsynaptic:Inhibited signal detection
Presynaptic:Neuronal signal
Memantine Treatment
Memantine: Mechanism of Action
Postsynaptic:Stabilized signaldetection
Presynaptic:Neuronal signal
Excess glutamate
GLUTAMATE
Excess glutamate
• Restoration of physiological signal transmission
• Memantine blocks effect of excess glutamate
Memantine
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
