1. Properties of Memantine and Mechanism of Action

2. Structural Formula of Memantine
1-amino-3,5-dimethyl-adamantane
NH3+
CH3
H3C
Memantine (1-amino-3,5-dimethyladamantane) is a moderate affinity uncompetitive N-methyl-D-aspartate (NMDA) receptor channel blocker.
The pharmacological features (strong voltage-dependency and fast blocking/unblocking kinetics) allow memantine to block sustained activation by micromolar concentrations of glutamate under pathological conditions. On the other hand, memantine rapidly leaves the NMDA channel upon transient physiological activation by millimolar concentrations of presynaptically released glutamate. These features are thought to be responsible for the good tolerability observed in clinical use.
Memantine is likely to show neuroprotective effects at therapeutic concentrations used in the treatment of Alzheimer’s disease (AD) and to slow down disease progression. As shown in preclinical experiments memantine produces improvements in neuronal plasticity and learning under conditions of tonic NMDA receptor activation which is suggested to occur in AD.

3. Memantine is a NMDA Receptor Channel Antagonist
(³H)-MK-801 binding to homogenates of postmortem human cortex
100 80 60 40 20
 Memantine Ki = 0.54 ± 0.04 µM
 MK-801 Ki = ± µM
Specific (3H)-MK-801 Binding (%)
The uncompetitive N-methyl-D-aspartate (NMDA) receptor channel antagonist memantine inhibits the binding of [3H](+)MK-801 to postmortem human brain homogenates at therapeutically used concentrations.
Tissue from the frontal cortex has been taken at autopsy 24 to 48 hours postmortem from 3 individuals. The values in this figure are the means of triplicate determinations in a single representative experiment. The experiment was repeated 3 times, using homogenates from the different brains, with very similar results. Both (+)MK-801 (dizocilpine, a high-affinity NMDA receptor antagonist) and memantine completely inhibited [3H](+)MK-801 binding at 100 µM. As seen in an earlier investigation, the displacement curves with (+)MK-801 had Hill coefficients less than unity (0.42  0.03) and were best fitted by assuming an interaction with two binding sites (Ki1 = 1,20  0.15 nM, Ki2 = 10,70  0.81 µM; p < 0.05). The displacement curves produced by memantine had Hill coefficients near unity (0.98  0.06) and were best fitted with a one-site model (Ki = 0.54  0.04 µM).
The data represent that the uncompetitive NMDA receptor antagonist memantine is active at the (+)MK-801 binding site.
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
(+)MK-801 shows very slow blockade of NMDA receptors
Memantine shows fast blockade of NMDA receptors
Mg2+ shows very fast blockade of NMDA receptors
and also slow unblockade
and also fast unblockade
and also relatively fast unblockade
Mg2+
Memantine
MK-801
Animated Slide! (Automatic!)
Kinetic properties of the NMDA (N-methyl-D-aspartate) receptor antagonist memantine were compared to the physiological NMDA receptor channel blocker magnesium and the high-affinity NMDA receptor antagonist dizocilpine ((+)MK-801). The compounds were tested on cultured superior collicular neurons by using the patch clamp technique.
Kinetic properties of memantine, magnesium and (+)MK-801 in blocking NMDA induced currents responses were tested in whole cell patch clamp recordings. The effects of memantine have been compared to the physiological NMDA channel blocker magnesium and the high affinity NMDA channel blocker dizocilpine ((+)MK-801) under similar conditions. In the first figure (left) Mg2+ (1.5 mM) was continuously present for 3 min. Note the almost instantaneous onset of, and recovery from, the channel blocking effects of Mg2+ (low affinity and fast blocking and unblocking kinetics). (+)MK-801 (1 µM; right) was continuously present for 7 min as indicated by the blue bar. No recovery from the effects of (+)MK-801 was seen even after 10 NMDA applications following removal of the antagonist (high affinity and slow blocking and unblocking kinetics). Memantine (16 µM; middle) was continuously present for 2.5 min. In contrast to (+)MK-801, memantine (moderate affinity and fast blocking and fast unblocking kinetics) blocked the NMDA induced current with kinetic properties between those of magnesium and (+)MK-801.
Magnesium shows low affinity which is associated with fast blocking/unblocking kinetics. In contrast, dizolcipine reveals very high affinity which is associated with very slow kinetics. With its moderate affinity memantine shows kinetics which are between magnesium and (+)MK-801.
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
 Memantine
 Mg2+
 MK-801
Control Response (%)
The graph shows pooled data from electrophysiological recordings performed with the “patch clamp” technique at different holding potentials. Such conditions mimic different synaptic status: resting conditions (negative potentials), pathological activation (moderate but prolonged synaptic activity at slightly depolarized potentials) and physiological synaptic transmission (strong but short lasting synaptic activity at strongly depolarized potentials).
The electrophysiological studies revealed that the moderate potency of memantine is associated with a voltage-dependency between those of Mg2+ and (+)MK-801. As a result of its lower voltage-dependency, memantine is more effective than Mg2+ in blocking tonic pathological activation of NMDA receptors at moderately depolarized membrane potentials. Following strong synaptic activation, memantine like Mg2+, can leave the NMDA receptor channel due to its voltage-dependency and fast unblocking kinetics.
Memantine suppresses synaptic noise but allows the relevant physiological synaptic signal to be detected. This provides both neuroprotection and restoration of synaptic plasticity by the same drug.
resting
condition
pathological
activation
physiological
synaptic transmisson
Increasing membrane potential
Parsons et al., Neuropharmacology 1993

6. Properties of Memantine
Resting
Condition
(- 70mV)
Pathological
Condition
(- 50mV)
Physiological synaptic
Neurotransmission
(- 20mV)
Ca2+
Ca2+
Magnesium
Ca2+
The scheme shows the different kinetic and voltage-dependent properties of the physiological channel blocker Mg2+, the moderate affinity channel blocker memantine and the high affinity channel blockers dizocilpine ((+)MK-801) or phencyclidine (PCP) at the NMDA (N-methyl-D-aspartate) receptor. The processes are presented during resting conditions, physiological synaptic activity and under conditions of pathological moderate membrane depolarization.
Under resting conditions and in their continuing presence, both Mg2+ and memantine block the NMDA channel. Likewise, both are able to leave the NMDA receptor channel upon strong synaptic depolarization due to their pronounced voltage-dependency and fast unblocking kinetics. In contrast to Mg2+ memantine does not leave the channel so easily upon moderate prolonged depolarization during chronic excitotoxic insults.
High affinity NMDA channel blockers like (+)MK-801 or PCP have much slower unblocking kinetics and less pronounced voltage-dependency than Mg2+ or memantine. They are therefore unable to leave the channel within the time course of a normal NMDA receptor mediated excitatory postsynaptic potential. As a result, high affinity channel blockers like (+)MK-801 or PCP block both the pathological and the physiological activation of NMDA receptors.
Under pathological conditions, i.e. continuous moderate membrane depolarization due to elevated glutamate concentrations, Mg2+ leaves the voltage-dependent channel of the NMDA receptor. This unblocking process leads to prolonged excessive Ca2+ influx leading to increased noise and cognitive decline in patients with Alzheimer’s disease. In contrast to the pseudo-irreversible blockade of high affinity channel blockers like (+)MK-801 or PCP, memantine effectively blocks the NMDA channel under pathological conditions, but preserves the physiological synaptic transmission.
Memantine
MK-801, PCP
Parsons et al., Neuropharmacolgy 1999 (mod. from Kornhuber)

7. AXURA: Mechanism of Action
Normal Situation
Postsynaptic:
Detected signal
Presynaptic:
Neuronal signal
GLUTAMATE
Glutamate transmits signal via
the NMDA receptor
Animated slide!
70% of all excitatory neurons use glutamate as neurotransmitter. Therefore, the signal transduction via glutamate is essential for intact execution of all CNS functions, especially those of cognitive processes.
An incoming signal is transmitted from the presynaptic neuron to the postsynaptic neuron by glutamate via the NMDA receptor. Hereby, glutamate is released into the synaptic cleft in a definite concentration and for a limited time.
It is essential for intact signal transduction that the released glutamate is cleared from the synaptic cleft by recycling via uptake into glia cells after termination of signal transduction. Under these conditions the glutamate-mediated signal can be detected in the postsynaptic neuron. This ensures that e.g. cognitive processes are intact.
Recycling of glutamate in glia cell

8. AXURA: Mechanism of Action
Alzheimer’s Disease
ß-Amyloid
ß-Amyloid inhibits glutamate recycling
Presynaptic:
Neuronal signal
Postsynaptic:
Inhibited signal detection
GLUTAMATE
Animated slide!
One of the hallmarks of Alzheimer’s disease is the deposition of beta-amyloid plaques. These plaques disturb the recycling of glutamate by inhibition of the uptake into the glia cell.
The signal which is mediated by glutamate is masked by the excess of glutamate. The toxic effect of excess glutamate leads to a disturbance of signal transmission which ultimately results e.g. in cognitive dysfunctions and, subsequently, impaired activities of daily living.
Excess glutamate masks signal
transmission

9. AXURA: Mechanism of Action
AXURA Treatment
ß-Amyloid
Presynaptic:
Neuronal signal
AXURA blocks effect of excess glutamate
Postsynaptic:
Stabilized signal detection
GLUTAMATE
Animated slide!
AXURA is the one and only NMDA (N-Methyl-D-Aspartate) receptor antagonist for the treatment of Alzheimer’s disease with a unique mechanism of action.
In Alzheimer’s disease AXURA blocks the toxic effect of excess glutamate in the synaptic cleft. If an incoming signal shall be transmitted by defined glutamate release from the presynaptic neuron, AXURA enables the postsynaptic neuron to detect this signal. Thus, AXURA protects the postsynaptic neuron from excess glutamate without inhibiting the physiological signal transmission. This ensures stabilized signal detection leading to e.g. improved/stabilized cognition and capabilities to conduct activities of daily living.
Restoration of physiological signal transmission

10. Memantine: Mechanism of Action
Normal Situation
Postsynaptic:
Detected signal
Presynaptic:
Neuronal signal
GLUTAMATE
Glutamate transmits signal via
the NMDA receptor
Animated slide!
70% of all excitatory neurons use glutamate as neurotransmitter. Therefore, the signal transduction via glutamate is essential for intact execution of all CNS functions, especially those of cognitive processes.
An incoming signal is transmitted from the presynaptic neuron to the postsynaptic neuron by glutamate via the NMDA receptor. Hereby, glutamate is released into the synaptic cleft in a definite concentration and for a limited time.
It is essential for intact signal transduction that the released glutamate is cleared from the synaptic cleft by recycling via uptake into glia cells after termination of signal transduction. Under these conditions the glutamate-mediated signal can be detected in the postsynaptic neuron. This ensures that e.g. cognitive processes are intact.
Recycling of glutamate in glia cell

11. Memantine: Mechanism of Action
Alzheimer’s Disease
ß-Amyloid
ß-Amyloid inhibits glutamate recycling
Presynaptic:
Neuronal signal
Postsynaptic:
Inhibited signal detection
GLUTAMATE
Animated slide!
One of the hallmarks of Alzheimer’s disease is the deposition of beta-amyloid plaques. These plaques disturb the recycling of glutamate by inhibition of the uptake into the glia cell.
The signal which is mediated by glutamate is masked by the excess of glutamate. The toxic effect of excess glutamate leads to a disturbance of signal transmission which ultimately results e.g. in cognitive dysfunctions and, subsequently, impaired activities of daily living.
Excess glutamate masks signal
transmission

12. Memantine: Mechanism of Action
Memantine Treatment
ß-Amyloid
Presynaptic:
Neuronal signal
Memantine blocks effect excess glutamate
Memantine
Postsynaptic:
Stabilized signal detection
GLUTAMATE
Animated slide!
Memantine is the one and only NMDA (N-Methyl-D-Aspartate) receptor antagonist for the treatment of Alzheimer’s disease with a unique mechanism of action.
In Alzheimer’s disease memantine blocks the toxic effect of excess glutamate in the synaptic cleft. If an incoming signal shall be transmitted by defined glutamate release from the presynaptic neuron, memantine enables the postsynaptic neuron to detect this signal. Thus, memantine protects the postsynaptic neuron from excess glutamate without inhibiting the physiological signal transmission. This ensures stabilized signal detection leading to e.g. improved/stabilized cognition and capabilities to conduct activities of daily living.
Restoration of physiological signal transmission

13. AXURA: Mechanism of Action
Normal Situation
Postsynaptic:
Detected signal
Presynaptic:
Neuronal signal
GLUTAMATE
Glutamate as signal transmitter
Animated slide!
70% of all excitatory neurons use glutamate as neurotransmitter. Therefore, the signal transduction via glutamate is essential for intact execution of all CNS functions, especially in cognitive processes.
An incoming signal is transmitted from one neuron to the other via glutamate. Under healthy/ normal conditions this signal is detected by the subsequent neuron. Only if the signal transmission is intact, it is ensured that e.g. cognitive processes are intact.

14. AXURA: Mechanism of Action
Alzheimer’s Disease
GLUTAMATE
Excess glutamate masks signal
transmission
Excess glutamate
Presynaptic:
Neuronal signal
Postsynaptic:
Inhibited signal
detection
Animated slide!
In Alzheimer’s disease there is an excess of glutamate which masks the signal transmission from one neuron to the other. The toxic effect of excess glutamate leads to a disturbance of signal transmission which ultimately results e.g. in cognitive dysfunctions and, subsequently, impaired activities of daily living.

15. AXURA: Mechanism of Action
AXURA Treatment
Excess glutamate
GLUTAMATE
Presynaptic:
Neuronal signal
AXURA blocks effect of excess glutamate
Postsynaptic:
Stabilized signal
detection
Animated slide!
AXURA is the one and only NMDA (N-Methyl-D-Aspartate) receptor antagonist for the treatment of Alzheimer’s disease with a unique mechanism of action.
In Alzheimer’s disease AXURA blocks the toxic effect of excessive glutamate. This leads to a stabilized signal transduction. This stabilizes signal detection and ensures that function of e.g. cognitive processes are restored.
Restoration of physiological signal transmission

16. Memantine: Mechanism of Action
Normal Situation
Postsynaptic:
Detected signal
Presynaptic:
Neuronal signal
GLUTAMATE
Glutamate as signal transmitter
Animated slide!
70% of all excitatory neurons use glutamate as neurotransmitter. Therefore, the signal transduction via glutamate is essential for intact execution of all CNS functions, especially in cognitive processes.
An incoming signal is transmitted from one neuron to the other via glutamate. Under healthy/ normal conditions this signal is detected by the subsequent neuron. Only if the signal transmission is intact, it is ensured that e.g. cognitive processes are intact.

17. Memantine: Mechanism of Action
Alzheimer’s Disease
GLUTAMATE
Excess glutamate masks signal
transmission
Excess glutamate
Presynaptic:
Neuronal signal
Postsynaptic:
Inhibited signal
detection
Animated slide!
In Alzheimer’s disease there is an excess of glutamate which masks the signal transmission from one neuron to the other. The toxic effect of excess glutamate leads to a disturbance of signal transmission which ultimately results e.g. in cognitive dysfunctions and, subsequently, impaired activities of daily living.

18. Memantine: Mechanism of Action
Memantine Treatment
GLUTAMATE
Excess glutamate
Excess glutamate
Presynaptic:
Neuronal signal
Memantine blocks effect of excess glutamate
Memantine
Postsynaptic:
Stabilized signal
detection
Animated slide!
Memantine is the one and only NMDA (N-Methyl-D-Aspartate) receptor antagonist for the treatment of Alzheimer’s disease with a unique mechanism of action.
In Alzheimer’s disease memantine blocks the toxic effect of excessive glutamate. This leads to a stabilized signal transduction. This stabilizes signal detection and ensures that function of e.g. cognitive processes are restored.
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
Since memantine and magnesium are similar in their properties concerning the NMDA receptor, the question might occur, whether memantine treatment can be replaced by administration of magnesium. The reasons given in the slide and below cover the main aspects why treatment with magnesium is no alternative to memantine treatment.
Potential side effects related to high magnesium levels
a) To obtain significant increases in brain magnesium concentration, very high parenteral doses of magnesium salts are needed (Hallak 1998). This may contribute to the occurrence of severe symptomatic hypermagnesemia, leading to loss of tendon reflexes and muscle weakness, junctional bradycardia, which may lead to cardiac arrest, hypotension (due to peripheral vasodilatation), flushing of the skin, parasympathetic blockade, fixed and dilated pupils and central nervous system effects (drowsiness, confusion, respiratory depression and coma) (reviewed by Fung et al., 1995).
Practical aspects
a) Parenteral administration for chronic use impairs patients’ quality of life.
b) Parenteral administration requires intensive monitoring due to the risks mentioned above.
Lack or doubtful efficacy of magnesium
a) Although magnesium deficit was implicated in the pathogenesis of dementia (particularly Alzheimer’s disease), it was also suggested, that magnesium supplementation cannot prevent or treat this disorder (Durlach 1990).
b) No clinical studies on the efficacy of magnesium in dementia available.
The use of magnesium is NOT recommended in Alzheimer’s diease
a) Potential interaction of magnesium with central cholinergic system, i.e. presynaptic inhibition of acetylcholine release (Fung et al., 1995) and diminution of muscarinic responses (Ladner and Lee 1999) may lead to cholinergic deficit and exert adverse effect in disorders associated with learning deficits (including Alzheimer’s disease).
b) It was suggested, that magnesium ions might contribute to excitotoxicity (Hartnett et al., 1997, Helpern et al., 1993, see Reynolds 1998 for review).