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

% S

pe

cifi

c [

3H

]-M

K-8

01

Bin

din

g

10.01 0.1 10 100

100

80

60

40

20

0

Memantine Ki = 0.54 ± 0.04 µM

MK-801 Ki = 0.0012 ± 0.00015 µM

Memantine is a NMDA Receptor Channel Antagonist

Concentration (µM)

Kinetics of NMDA-Receptor Blockade Intermediate between Mg2+ and MK-801

Mg 2+ shows very fast blockade of NMDA receptors and also fast unblockade

MK-801

(+)MK-801 shows very slow blockade of NMDA receptors

and also slow unblockade

Memantine shows fast blockade of NMDA receptors

MemantineMg 2+

Peaks represent responses to application of

NMDA

time

and also relatively fast unblockade

Parsons et al., Neuropharmacology 1993

Parsons et al., Neuropharmacology 1993

% C

on

tro

l Re

spo

nse

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

Memantine in Neurodegenerative Dementia

Memantine improvesplastic processes

signal

signal detected

learning M

noise

Ca2+

noise

Neuroprotectionby memantine

rest

Ca2+M

Pathological activationof NMDA receptors

rest

Ca2+

noise

GlutamateMagnesiumMemantineM

Danysz et al., Neurotox Res 2000

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