Mechanism of action of memantine
Jon W Johnson and Shawn E Kotermanski
Memantine is a clinically useful drug in many neurological
disorders, including Alzheimer’s disease. The principal
mechanism of action of memantine is believed to be the
blockade of current flow through channels of N-methyl-D-
aspartate (NMDA) receptors — a glutamate receptor subfamily
broadly involved in brain function. Surprisingly, other drugs that
block NMDA receptor channels, such as ketamine, exhibit
serious deleterious effects. The unusual therapeutic utility of
memantine probably results from inhibitory mechanisms
shared with ketamine, combined with actions specific to
memantine. These potentially important differences between
memantine and ketamine include effects on gating of blocked
channels and binding of memantine to two sites on NMDA
receptors. Because modulation of NMDA receptor activity can
increase or decrease excitability of neuronal circuits, subtle
differences in the mechanisms of action of NMDA receptor
antagonists can strongly impact on their clinical effects.
Addresses
Department of Neuroscience, University of Pittsburgh, Pittsburgh,
Pennsylvania, 15260, USA
Corresponding author: Johnson, Jon W (johnson@bns.pitt.edu)
Current Opinion in Pharmacology 2006, 6:61–67
This review comes from a themed issue on
Neurosciences
Edited by Alan Foster and John Kemp
Available online 20th December 2005
1471-4892/$ – see front matter
# 2006 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.coph.2005.09.007
Introduction
Although overactivation of N-methyl-D-aspartate recep-
tors (NMDARs) has been implicated in many neurode-
generative diseases [1], attempts to use NMDAR
antagonists as therapeutic agents often failed because
of debilitating side effects [2,3]. These side effects occur
because of the critical roles that NMDARs play in brain
functions, including synaptic communication and mem-
ory formation. Memantine (Figure 1a) has been hypothe-
sized to allow physiological activation of NMDARs while
inhibiting pathological overactivation as a result of its
mechanism of NMDAR inhibition.
Memantine has been a focus of attention because of its
recent approval in Europe and the US for use in moderate
to severe Alzheimer’s disease (AD) [4]. However, mem-
antine might have far broader therapeutic utility, and is
www.sciencedirect.com
effective in the treatment of other dementias [5] and
neurodegenerative diseases, including Parkinson’s [5,6]
and Huntington’s [7] diseases. Memantine also shows
promise as a treatment for other diseases associated with
excessive NMDAR activation in the central nervous
system (CNS), including glaucoma, multiple sclerosis,
epilepsy and neuropathic pain [2,5,6,8]. Further under-
standing of the mechanism of action of memantine might
help identify the properties responsible for its high clin-
ical potential, and hasten the development of other
therapeutic NMDAR antagonists.
Sites of action of memantine
Memantine was first synthesized in the 1960s, and was
found in the 1970s to affect the CNS [6]. In 1989,
memantine was found to inhibit NMDARs [9,10] with
an IC50 of approximately 1 mM [11–19], which corre-
sponds well with its therapeutic concentration range. In
the treatment of AD, memantine is typically adminis-
tered at 20 mg/d [4]. Following administration of 5–
30 mg/d of memantine in humans, cerebrospinal fluid
concentrations of 0.05–0.31 mM were measured 2–3 hours
after the last dose; serum concentrations were about
twofold higher [20]. NMDARs are ubiquitous within
the vertebrate CNS, and are involved in a remarkable
variety of physiological functions and pathological states
[21–23]. The idea that the principal target of memantine
is a receptor involved in the etiology of many nervous
system diseases was, and remains, highly attractive [6,24–
26,27]. Thus, the discovery that memantine inhibits
NMDARs initiated a continuing flood of studies.
At high concentrations (10–500 mM), memantine affects
many CNS targets, including serotonin and dopamine
uptake, nicotinic acetylcholine receptors (nAChRs), ser-
otonin receptors, sigma-1 receptors, and voltage-activated
Na+ channels [28,29]. In addition, higher affinity actions
have been observed on specific subtypes of nAChRs and
5-hydroxytryptamine (5-HT) receptors. The nAChR sub-
unit combinations that have been shown to be most
sensitive to memantine (with the memantine IC50, esti-
mated at 70 mV if possible, given in parentheses) are:
a4/b2 heteromers (14 mM) [30], a9/a10 heteromers
(1.6 mM) [31] and a7 homomers (5 mM [32] or 0.34 mM
[33]). The significant discrepancy between the IC50
estimates for homomeric a7 receptors might result from
experimental differences (recombinant human receptors
expressed in Xenopus oocytes [32] versus native receptors
in rat hippocampal neurons [33]) or inclusion of sub-
units other than a7 in the native receptors [33]. Inhibi-
tion of nAChRs is unlikely to augment the therapeutic
action of memantine, as loss of cholinergic neurons is a
Current Opinion in Pharmacology 2006, 6:61–67
62 Neurosciences
Figure 1
Memantine and NMDARs. (a) Structure of memantine. (b) Diagram
depicting the four-subunit quaternary structure of NMDARs (upper
panel), and the transmembrane structure (lower panel) of two NMDAR
subunits (shown in blue, with the front and back subunits removed for
clarity; note that the actual arrangement of subunits is not firmly
established), with glycine (green) bound to the NR1 subunit, glutamate
(also green) bound to the NR2 subunit, and memantine (red) blocking the
channel. The N-sites, asparagine residues critically involved in channel
blockade by Mg2+ and many organic blockers, are identified with
asterisks. Locations of amino acids at which mutations cause greater
than a threefold change in memantine IC50 are identified by black dots.
These amino acids, based on experiments with receptors composed of
NR1 and NR2B (one of the four NR2 subunit subtypes) subunits [19], are
N616 (the N-site), A645, Y647, A653 and V656 in NR1; and W607, N615
(the N-site) and N616 in NR2B. Identical or homologous amino acids
confirmed as important in memantine channel blockade based on
experiments with receptors composed of NR1 and NR2A subunits [45]
are N616 and A645 in NR1; N614 (the N-site) and N615 in NR2A.
hallmark of AD [25,33] (but see [34]) and behavioral
studies suggest that memantine does not have anticholi-
nergic effects at clinically useful concentrations [35].
Memantine also inhibits steady-state 5-HT3 receptor
responses with an IC50 of 2.3 mM, an action that might
contribute to its therapeutic efficacy [36].
Current Opinion in Pharmacology 2006, 6:61–67
Properties of NMDARs
NMDARs are heteromeric ligand-gated ion channels
composed of four subunits (Figure 1b) [21]. Three
NMDAR subunit families have been described: NR1,
NR2 and NR3. Functional glutamate-dependent
NMDARs must contain NR1 and NR2 subunits; NR3
subunits are not obligatory and modulate NMDAR prop-
erties [37]. NMDARs require occupation by two types of
agonists for channel activation: a glutamate site agonist at
NR2 subunits, and a glycine site agonist at NR1 subunits
(Figure 1b).
The channels of NMDARs exhibit two unusual proper-
ties: voltage-dependent channel block by endogenous
Mg2+, and high permeability to Ca2+. Channel block by
Mg2+ inhibits more than 90% of the NMDAR-mediated
current at typical neuronal resting potentials. However,
postsynaptic depolarization changes the voltage field
across the channel, forcing Mg2+ out and enhancing
NMDAR-mediated currents. Thus, effective conduction
of current through NMDARs requires two coincident
signals — presynaptic release of glutamate and postsy-
naptic depolarization — allowing NMDARs to act as
‘coincidence detectors’.
The second unusual property of NMDAR channels —
high Ca2+ permeability — endows NMDAR activity with
profound physiological and pathological significance.
Coincident pre- and post-synaptic activity stimulates
Ca2+ influx through NMDARs, activating an array of
intracellular signaling pathways with diverse potential
consequences, including stabilization of synaptic connec-
tions, long-term depression or long-term potentiation of
synaptic strength, and either necrotic or apoptotic neu-
ronal death [22,38–41]. Thus, inhibition of NMDAR
activity can have vastly divergent consequences, which
can be either deleterious or beneficial.
Channel block of NMDA receptors by
memantine
Memantine works by blocking the channel of NMDARs
(Figure 1b) [10–17,42–44]. Memantine is classified as an
‘open channel blocker’ because it can enter the channel
and block current flow only after channel opening. Over-
lap of the sites where memantine and Mg2+ bind is
suggested by the following two observations: Mg2+
decreases blockade by memantine [17], and mutation
of ‘N-site’ asparagines — residues in the M2 region of
NR1 and NR2 subunits that are critical for Mg2+ block —
also strongly affects memantine block [19]. Other muta-
tions [19,45,46] have distinct effects on the block by
Mg2+ and memantine (Figure 1b), implying differences in
access or binding sites.
After memantine blocks the channel of NMDARs, the
channel can close and agonists can unbind, ‘trapping’
memantine inside the channel (Figure 2a) [14,15]. Many
www.sciencedirect.com
 Mechanism of action of memantine Johnson and Kotermanski 63
Figure 2
Schematic models of channel blockade of NMDARs. Colours of symbols
correspond to Figure 1. (a) Trapping model: an NMDAR (R) must bind
multiple agonist molecules (A), probably two glutamate and two
glycines, to reach state AnR. Subsequently, multiple structural
rearrangements lead to channel opening (AnR*). The blocker molecule
then can bind in the open channel (AnR*B); the channel can close on the
blocker (AnRB); and agonist can unbind, trapping the blocker (RB). (b)
‘Sequential’ or ‘foot-in-the-door’ model: because blocker binding
prevents channel closure, AnRB and RB states are not accessible to this
type of blocker.
‘trapping channel blockers’ of NMDARs have been
described, including MK-801, phencyclidine, ketamine
and amantadine [2]. Several other channel blockers are
thought to prevent channel closure, and thus are bound in
the NMDAR channel only when it is open (Figure 2b)
[44,47]. Such blockers are called ‘sequential’ or ‘foot-in-
the-door’ blockers.
Channel blockers also are sometimes, although inconsis-
tently, referred to as non-competitive or uncompetitive.
Because channel blockers do not compete for binding to
agonist binding sites, they can be generically called non-
competitive antagonists (in contrast to competitive
antagonists such as D-2-amino-5-phosphonovaleric acid
(APV), which binds to the glutamate site). However,
these channel blockers can be further divided into two
separate subgroups: uncompetitive and, again, non-com-
petitive. This second use of non-competitive creates
obvious potential for confusion. The distinction between
uncompetitive and non-competitive mechanisms derives
from enzyme kinetics: inhibitors that can be bound only
to an enzyme–substrate complex (analogous to state AnR*
in Figure 2) are uncompetitive, whereas inhibitors that
bind equally well to all enzymatic states are non-compe-
titive. Further confusion of antagonist terminology has
resulted from two subtly different applications of ‘uncom-
petitive’ to channel blockers. The first definition — ‘an
antagonist that can be bound to the receptor only when the
channel is open’ — corresponds to uncompetitive enzyme
inhibitors, and includes only sequential blockers
(Figure 2a). The second — ‘antagonists that can bind to
the receptor only when the channel is open’ — includes
both sequential and trapping blockers (Figure 2b),
www.sciencedirect.com
antagonists with potentially diverse characteristics (see
below). By the first definition, memantine is not an
uncompetitive antagonist, because it can be trapped.
By the second definition, memantine is an uncompetitive
antagonist. Both definitions of uncompetitive are used
commonly to describe the mechanism of memantine
action (e.g. [6,13,15,25,26,42,43]). Because of the confu-
sion created by the various definitions of non-competitive
and uncompetitive, we find it best to avoid their applica-
tion to channel blockers.
Mechanistic differences between
memantine and ketamine
A critical and unresolved question is why memantine,
among the many NMDAR antagonists that have been
tested in humans, is of unusual therapeutic utility. A host
of intersecting hypotheses have been proposed to identify
properties of memantine that endow it with clinical safety
and efficacy, including the ability to bind only (or pre-
ferentially) to open channels; the tendency to inhibit
faster, or with higher affinity, at higher agonist concen-
trations; a relatively low affinity of inhibition; relatively
fast unblocking kinetics; relatively strong voltage depen-
dence; an ability to be trapped in some but not all
receptors; an ability to inhibit at two different sites;
and NMDAR subtype specificity, or lack thereof. The
clinical utility of memantine probably results from a
combination of these properties, and numerous reviews
have explored the hypothetical relationship between the
properties of memantine and its therapeutic effects
[3,6,8,25,26,28]. To limit and focus the rest of this review,
we concentrate on differences between memantine and
ketamine, two drugs that appear to have strikingly similar
channel blocking properties, but dissimilar clinical
effects. Both drugs are trapping blockers of NMDARs,
and thus bind exclusively or preferentially to open chan-
nels and inhibit with faster kinetics at higher agonist
concentrations. The IC50 of ketamine is about half that
of memantine; the blocking and unblocking kinetics and
voltage dependence also are similar [12,13,43,48], and
neither drug appears to exhibit strong NMDAR subtype
specificity [11,18,49].
It is likely that some of the properties shared by mem-
antine and ketamine are required for the clinical utility of
memantine. However, despite their similarities, the ther-
apeutic potential of these drugs is strongly divergent.
Ketamine causes memory deficits; reproduces with
impressive accuracy the symptoms of schizophrenia; is
widely abused; and induces vacuoles in neurons at mod-
erate concentrations and cell death at higher concentra-
tions [23,50]. Memantine, on the other hand, is well
tolerated; although instances of psychotic side effects have
been reported, in placebo-controlled clinical studies the
incidence of side effects is remarkably low [4,6,25,51].
Memantine improves memory in AD patients and in some
(but not all) studies in animals; does not appear to have
Current Opinion in Pharmacology 2006, 6:61–67
64 Neurosciences
abuse potential, but rather has shown promise in treating
addiction; and, although both drugs can be neuroprotective
at low doses and neurotoxic at high doses, memantine
exhibits much weaker neurotoxicity [4,6,13,25,26,52,53].
How can two drugs that act by such similar mechanisms
have such different effects? One possible explanation is
pharmacokinetic differences: memantine is eliminated, for
example, much more slowly than ketamine. The elimina-
tion half-lives in human serum are: memantine (oral), 60–
80 h [51]; ketamine (imtravenous or oral), 2.5 h [54,55].
The faster pharmacokinetics of ketamine might lead to the
use of doses that cause a concentration spike resulting in
psychotomimetic effects. However, the psychotomimetic
effects of ketamine have been demonstrated [56] by a
continuous 40 min intravenous administration of ketamine
at 0.0125 mg/kg/min (total dose, 0.5 mg/kg), a procedure
that should minimize concentration spikes. Furthermore,
phencyclidine exhibits even stronger psychotomimetic
effects than does ketamine [23,25], despite its longer
elimination half-life (7–51 hours via multiple routes of
administration [57]). Thus, we find it unlikely that phar-
macokinetic differences can fully explain the different
clinical utilities of memantine and ketamine. We will
explore two other possible explanations for the clinical
disparity of memantine and ketamine: differences in their
effects on NMDAR transitions among blocked states, and
differences in their ability to bind at multiple sites on
NMDARs.
Transitions among blocked states of a receptor (states
AnR*B, AnRB and RB in Figure 2) have a surprisingly
powerful effect on the inhibitory properties of a blocker.
For example, if a trapping blocker (Figure 2a) and a
sequential blocker (which does not permit transitions
among blocked states; Figure 2b) have equal affinities
for the open channel, the trapping blocker can inhibit
responses with a much lower IC50 [47,58]. Furthermore,
because a sequential blocker can only be bound to open
channels, it inhibits most effectively (with the lowest
IC50) channels that spend longest in the open state
(i.e. receptors with the highest Popen). A potential benefit
is that, as glutamate concentration increases (e.g. during
an ischemic insult), the antagonist becomes more effec-
tive. However, depending upon a blocker’s kinetics, it
might inhibit synaptic transmission most effectively, as
glutamate concentrations are highest during synaptic
responses. Trapping blockers, conversely, can partly inhi-
bit, have no effect on, or even encourage channel closure.
The clinically useful drug amantadine, an analog of
memantine, is a trapping blocker that encourages channel
closure [59].
Data on the effects of memantine and ketamine on
channel gating are limited. Memantine inhibition has
been observed to increase with agonist concentration
[12,33,42], an effect consistent with partial inhibition
Current Opinion in Pharmacology 2006, 6:61–67
of channel closure [47]. The measurements, however,
vary considerably. This variability might arise because
channel blocking kinetics increase with agonist concen-
tration: at low agonist concentrations, kinetics can be slow
and inhibition can appear weak if measurements are
made too early. The observation of ‘partial trapping’ of
memantine is also consistent with partial inhibition of
channel closure. When agonist and a high concentration
of memantine are applied to a neuron, nearly all NMDAR
channels become blocked. If agonist and memantine are
then simultaneously removed, some blocked channels do
not trap memantine [14]. Partial trapping can result from
partial inhibition of channel closure because the resulting
increase in channels in the open, blocked state (AnR*B in
Figure 2a) allow more blocker to unbind before channel
closure [14]. However, alternative explanations for partial
trapping have been proposed, including closed-channel
egress of blocker [60] (see [61,62] for related discussion)
and the presence of a second memantine binding site (see
below). The mechanism that underlies memantine partial
trapping might be important to its therapeutic use, as
incomplete trapping can increase the number of
NMDARs available to support repetitive synaptic inputs.
Interestingly, a higher percentage of blocked channels
trap ketamine than they do memantine [43], suggesting
the two drugs may have differential effects on channel
gating. Divergent effects of chemical modification of
NMDARs on the inhibition by memantine and ketamine
[46] also support the idea that these drugs affect channel
gating differently.
The second characteristic to be discussed here that could
be important in explaining the functional differences
between memantine and ketamine is the ability of mem-
antine to bind at a shallow, as well as a deep, site
[14,16,17]. There is not general agreement on the char-
acteristics of the shallow site; although memantine can
interact with a shallow site in the absence of agonist [14],
other data suggest that a shallow site can be occupied only
when the channel is open [16,44]. This conflict might be
partly resolved by the suggestion that occupation of the
shallow site in the absence of agonist can induce channel
opening [17]. Although the IC50 of memantine for this
shallow site appears to be >100 mM, the ability of mem-
antine to bind to two sites (an ability that has not been
reported for ketamine) might have important conse-
quences for its inhibitory effects. Further investigation
of the functional implications of this shallow memantine
binding site is needed.
The importance of Mg2+ to understanding
channel-blocking drugs
Most studies of memantine block have been performed in
the absence of Mg2+. It will be important in future studies
to examine carefully the interaction between Mg2+ and
memantine. If Mg2+ and memantine cannot bind simul-
taneously, as appears likely, then Mg2+ and memantine
www.sciencedirect.com
 Mechanism of action of memantine Johnson and Kotermanski 65
must compete for binding. Thus, at resting potential in
physiological Mg2+ concentrations, the IC50 of memantine
(or any similar channel blocker) should be strongly
increased, and therapeutic memantine concentrations
should have negligible effects on NMDAR responses.
Depolarizations that relieve Mg2+ block should increase
inhibition by memantine because the voltage dependence
of memantine inhibition is weaker than that of Mg2+. Large
depolarization, however, would increase the IC50 of mem-
antine to values far above therapeutic concentrations.
Thus, significant effects of channel blockers at physiolo-
gical Mg2+ concentrations would be predicted only in
moderately depolarized neurons, and not during ‘normal’
synaptic transmission at potentials near resting potential.
Enigmatic clinical effects of memantine
It is surprising that a glutamate receptor antagonist can
improve the symptoms of AD, a disease characterized by
deficits in the levels of both glutamate and glutamate
receptors [27]. The idea that memantine can slow the
long-term progression of AD through neuroprotective
actions is consistent with the ability of memantine to
inhibit NMDAR responses. However, memantine also
exhibits therapeutic effects, such as improvements in
cognitive abilities, after as little as two weeks of treatment
[2]. Several explanations for the cognitive benefits of
memantine in AD have been proposed, including a
decrease in synaptic ‘noise’ resulting from excessive
NMDAR activation [6], inhibition of b-amyloid produc-
tion or toxicity [25], and readjustment of the balance
between inhibition and excitation [27]. The last hypoth-
esis, which relies on NMDAR actions on neuronal net-
works, might also be relevant to neurotoxic NMDAR
channel blockers such as MK-801, phencyclidine and
ketamine. These antagonists have been proposed to kill
neurons by reducing activity of inhibitory interneurons that
depend heavily on NMDARs for their activation, resulting
in disinhibition of excitatory neurons [50]. Because the
activity and plasticity of both excitatory and inhibitory
neurons depend critically on NMDARs, subtle variations
in the action of an NMDAR inhibitor can cause great
variations in its network effects. Furthermore, the balance
between synaptic and extrasynaptic NMDAR activation
can determine whether neuron survival or death is encour-
aged [22]. Thus, it is not surprising that inhibitors which
appear to differ mechanistically even as little as memantine
and ketamine can exhibit such divergent therapeutic
potential.
Conclusions
Memantine is an NMDAR antagonist with clinical utility
in many nervous system diseases, of which the most
prominent currently is AD, a disease characterized by
deficits in glutamatergic neurotransmission. The surpris-
ing therapeutic effects of memantine contrast strongly
with the deleterious effects of ketamine, an NMDAR
antagonist with channel-blocking characteristics similar
www.sciencedirect.com
to those of memantine. The beneficial effects of mem-
antine and the neurotoxic effects of ketamine might
derive, in part, from shifts in the balance of the powerful
influences of NMDARs on excitation and inhibition in
the brain. Thus, apparently minor differences in the
mechanism of action of a drug can translate into great
differences in its clinical effects. Potentially important
mechanistic differences between memantine and keta-
mine include effects on channel function and the ability
of memantine to bind to two distinct sites on NMDARs.
However, a clear explanation for the clinical effectiveness
of memantine is yet to be developed. A characteristic of
memantine that deserves further investigation is its prob-
able competition with Mg2+, which should allow it (like
other channel blocking drugs) to have significant effects
only in moderately depolarized neurons. Deeper under-
standing of the mechanisms of action of NMDAR chan-
nel blockers could lead to improved therapeutic strategies
for numerous neurological disorders.
Acknowledgements
The authors thank P Ascher, TA Blanpied, RJ Clarke and BA Siegler for
insightful comments on the manuscript. This work was supported by
NIH grant MH45817.
References and recommended reading
Papers of particular interest, published within the annual period of
review, have been highlighted as:
 of special interest
 of outstanding interest
1. Lodge D, Danysz W, Parsons CG: Ionotropic glutamate receptors
as therapeutic targets. Johnson City: FP Graham Pub; 2002.
2. Palmer GC: Neuroprotection by NMDA receptor antagonists
in a variety of neuropathologies. Curr Drug Targets 2001,
2:241-271.
3. Lipton SA: Failures and successes of NMDA receptor
antagonists: molecular basis for the use of open-channel
blockers like memantine in the treatment of acute and chronic
neurologic insults. NeuroRx 2004, 1:101-110.
4. Witt A, Macdonald N, Kirkpatrick P: Memantine hydrochloride.
Nat Rev Drug Discov 2004, 3:109-110.
5. Kilpatrick GJ, Tilbrook GS: Memantine. Merz. Curr Opin Investig
Drugs 2002, 3:798-806.
6. Parsons CG, Danysz W, Quack G: Memantine is a clinically
well tolerated N-methyl-D-aspartate (NMDA) receptor
antagonist — a review of preclinical data. Neuropharmacology
1999, 38:735-767.
7. Beister A, Kraus P, Kuhn W, Dose M, Weindl A, Gerlach M:
The N-methyl-D-aspartate antagonist memantine retards
progression of Huntington’s disease. J Neural Transm Suppl
2004:117-122.
8. Lipton SA: Paradigm shift in NMDA receptor antagonist drug
development: molecular mechanism of uncompetitive
inhibition by memantine in the treatment of Alzheimer’s
disease and other neurologic disorders. J Alzheimer’s Dis 2004,
6:S61-S74.
9. Bormann J: Memantine is a potent blocker of N-methyl-D-
aspartate (NMDA) receptor channels. Eur J Pharmacol 1989,
166:591-592.
10. Kornhuber J, Bormann J, Retz W, Hubers M, Riederer P:
Memantine displaces [3H]MK-801 at therapeutic
concentrations in postmortem human frontal cortex.
Eur J Pharmacol 1989, 166:589-590.
Current Opinion in Pharmacology 2006, 6:61–67
66 Neurosciences
11. Bresink I, Benke TA, Collett VJ, Seal AJ, Parsons CG, Henley JM,
Collingridge GL: Effects of memantine on recombinant rat
NMDA receptors expressed in HEK 293 cells. Br J Pharmacol
1996, 119:195-204.
12. Parsons CG, Gruner R, Rozental J, Millar J, Lodge D: Patch
clamp studies on the kinetics and selectivity of N-methyl-D-
aspartate receptor antagonism by memantine (1-amino-3,5-
dimethyladamantan). Neuropharmacology 1993, 32:1337-1350.
13. Parsons CG, Quack G, Bresink I, Baran L, Przegalinski E,
Kostowski W, Krzascik P, Hartmann S, Danysz W: Comparison of
the potency, kinetics and voltage-dependency of a series of
uncompetitive NMDA receptor antagonists in vitro with
anticonvulsive and motor impairment activity in vivo.
Neuropharmacology 1995, 34:1239-1258.
14. Blanpied TA, Boeckman FA, Aizenman E, Johnson JW: Trapping
channel block of NMDA-activated responses by amantadine
and memantine. J Neurophysiol 1997, 77:309-323.
15. Chen HS, Lipton SA: Mechanism of memantine block of NMDA-
activated channels in rat retinal ganglion cells: uncompetitive
antagonism. J Physiol 1997, 499:27-46.
16. Sobolevsky A, Koshelev S: Two blocking sites of amino-
adamantane derivatives in open N-methyl-D-aspartate
channels. Biophys J 1998, 74:1305-1319.
17. Sobolevsky AI, Koshelev SG, Khodorov BI: Interaction of
memantine and amantadine with agonist-unbound
NMDA-receptor channels in acutely isolated rat hippocampal
neurons. J Physiol 1998, 512:47-60.
18. Parsons CG, Danysz W, Bartmann A, Spielmanns P, Frankiewicz
T, Hesselink M, Eilbacher B, Quack G: Amino-alkyl-
cyclohexanes are novel uncompetitive NMDA receptor
antagonists with strong voltage-dependency and fast
blocking kinetics: in vitro and in vivo characterization.
Neuropharmacology 1999, 38:85-108.
19. Kashiwagi K, Masuko T, Nguyen CD, Kuno T, Tanaka I, Igarashi K,
Williams K: Channel blockers acting at N-methyl-D-aspartate
receptors: differential effects of mutations in the vestibule and
ion channel pore. Mol Pharmacol 2002, 61:533-545.
20. Kornhuber J, Quack G: Cerebrospinal fluid and serum
concentrations of the N-methyl-D-aspartate (NMDA) receptor
antagonist memantine in man. Neurosci Lett 1995, 195:137-139.
21. Dingledine R, Borges K, Bowie D, Traynelis SF: The glutamate
receptor ion channels. Pharmacol Rev 1999, 51:7-61.
22. Hardingham GE, Bading H: The Yin and Yang of NMDA receptor
signalling. Trends Neurosci 2003, 26:81-89.
23. Krystal JH, D’Souza DC, Petrakis IL, Belger A, Berman RM,
Charney DS, Abi-Saab W, Madonick S: NMDA agonists and
antagonists as probes of glutamatergic dysfunction and
pharmacotherapies in neuropsychiatric disorders.
Harv Rev Psychiatry 1999, 7:125-143.
24. Smith PF: Therapeutic N-methyl-D-aspartate receptor
antagonists: will reality meet expectation? Curr Opin Investig
Drugs 2003, 4:826-832.
25. Rogawski MA, Wenk GL: The neuropharmacological basis for
the use of memantine in the treatment of Alzheimer’s disease.
CNS Drug Rev 2003, 9:275-308.
26. Lipton SA: Paradigm shift in NMDA receptor antagonist drug
development: molecular mechanism of uncompetitive
inhibition by memantine in the treatment of Alzheimer’s
disease and other neurologic disorders. J Alzheimers Dis 2004,
6:S61-S74.
27. Schmitt HP: On the paradox of ion channel blockade
 and its benefits in the treatment of Alzheimer disease.
Med Hypotheses 2005, 65:259-265.
The effects of NMDA response inhibition on the balance between synap-
tic excitation and inhibition are hypothesized to explain the surprising
therapeutic utility of memantine in AD.
28. Danysz W, Parsons CG, Kornhuber J, Schmidt WJ, Quack G:
Aminoadamantanes as NMDA receptor antagonists and
antiparkinsonian agents–preclinical studies. Neurosci
Biobehav Rev 1997, 21:455-468.
Current Opinion in Pharmacology 2006, 6:61–67
29. Brau ME, Dreimann M, Olschewski A, Vogel W, Hempelmann G:
Effect of drugs used for neuropathic pain management on
tetrodotoxin-resistant Na(+) currents in rat sensory neurons.
Anesthesiology 2001, 94:137-144.
30. Buisson B, Bertrand D: Open-channel blockers at the human
alpha4beta2 neuronal nicotinic acetylcholine receptor.
Mol Pharmacol 1998, 53:555-563.
31. Oliver D, Ludwig J, Reisinger E, Zoellner W, Ruppersberg JP,
Fakler B: Memantine inhibits efferent cholinergic transmission
in the cochlea by blocking nicotinic acetylcholine receptors of
outer hair cells. Mol Pharmacol 2001, 60:183-189.
32. Maskell PD, Speder P, Newberry NR, Bermudez I: Inhibition of
human alpha 7 nicotinic acetylcholine receptors by open
channel blockers of N-methyl-D-aspartate receptors.
Br J Pharmacol 2003, 140:1313-1319.
33. Aracava Y, Pereira EF, Maelicke A, Albuquerque EX: Memantine
 blocks alpha7 nicotinic acetylcholine receptors more potently
than n-methyl-D-aspartate receptors in rat hippocampal
neurons. J Pharmacol Exp Ther 2005, 312:1195-1205.
Memantine at clinically relevant concentrations is reported to inhibit
native a7 nAChR responses.
34. Banerjee P, Samoriski G, Gupta S: Comments on ‘‘Memantine
blocks alpha7* nicotinic acetylcholine receptors more
potently than N-methyl-D-aspartate receptors in rat
hippocampal neurons’’. J Pharmacol Exp Ther 2005,
313:928-929 author reply 930-923.
35. Zakharova ES, Danysz W, Bespalov AY: Drug discrimination
analysis of NMDA receptor channel blockers as nicotinic
receptor antagonists in rats. Psychopharmacology (Berl) 2005,
179:128-135.
36. Rammes G, Rupprecht R, Ferrari U, Zieglgansberger W, Parsons
CG: The N-methyl-D-aspartate receptor channel blockers
memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes
antagonise 5-HT(3) receptor currents in cultured HEK-293 and
N1E-115 cell systems in a non-competitive manner. Neurosci
Lett 2001, 306:81-84.
37. Sasaki YF, Rothe T, Premkumar LS, Das S, Cui J, Talantova MV,
Wong HK, Gong X, Chan SF, Zhang D et al.: Characterization and
comparison of the NR3A subunit of the NMDA receptor in
recombinant systems and primary cortical neurons.
J Neurophysiol 2002, 87:2052-2063.
38. Aamodt SM, Constantine-Paton M: The role of neural activity in
synaptic development and its implications for adult brain
function. Adv Neurol 1999, 79:133-144.
39. Nicoll RA, Malenka RC: Expression mechanisms underlying
NMDA receptor-dependent long-term potentiation.
Ann N Y Acad Sci 1999, 868:515-525.
40. Olney JW: Excitotoxicity, apoptosis and neuropsychiatric
disorders. Curr Opin Pharmacol 2003, 3:101-109.
41. Perez-Otano I, Ehlers MD: Homeostatic plasticity and NMDA
receptor trafficking. Trends Neurosci 2005, 28:229-238.
42. Chen HS, Pellegrini JW, Aggarwal SK, Lei SZ, Warach S,
Jensen FE, Lipton SA: Open-channel block of N-methyl-D-
aspartate (NMDA) responses by memantine: therapeutic
advantage against NMDA receptor-mediated neurotoxicity.
J Neurosci 1992, 12:4427-4436.
43. Mealing GA, Lanthorn TH, Murray CL, Small DL, Morley P:
Differences in degree of trapping of low-affinity uncompetitive
N- methyl-D-aspartic acid receptor antagonists with
similar kinetics of block. J Pharmacol Exp Ther 1999,
288:204-210.
44. Bolshakov KV, Gmiro VE, Tikhonov DB, Magazanik LG:
Determinants of trapping block of N-methyl-d-aspartate
receptor channels. J Neurochem 2003, 87:56-65.
45. Chen HSV, Lipton SA: Pharmacological implications of
 two distinct mechanisms of interaction of memantine
with N-methyl-D-aspartate-gated channels. J Pharmacol Exp
Ther 2005, 314:961-971.
Covalent modification of mutant NMDARs with methanethiosulfonate
reagents is used to investigate the approximate location of the external
www.sciencedirect.com
 Mechanism of action of memantine Johnson and Kotermanski 67
memantine binding site, and mutagenesis is used to confirm the impor-
tance of some NMDAR amino acids to the deep memantine blocking site.
46. Yuan H, Erreger K, Dravid SM, Traynelis SF: Conserved structural
 and functional control of N-methyl-D-aspartate receptor
gating by transmembrane domain M3. J Biol Chem 2005,
280:29708-29716.
After methanethiosulfonate modification of mutant NMDA receptors,
receptor-mediated currents are observed even after removal of agonists.
Interaction of channel blockers, including memantine and ketamine, with
modified receptors suggests differences in the mechanism of block.
47. Johnson JW, Qian A: Interaction between channel blockers and
channel gating of NMDA receptors. Biologicheskie Membrany
2002, 19:17-22.
48. Parsons CG, Panchenko VA, Pinchenko VO, Tsyndrenko AY,
Krishtal OA: Comparative patch-clamp studies with freshly
dissociated rat hippocampal and striatal neurons on the
NMDA receptor antagonistic effects of amantadine and
memantine. Eur J Neurosci 1996, 8:446-454.
49. Yamakura T, Mori H, Masaki H, Shimoji K, Mishina M: Different
sensitivities of NMDA receptor channel subtypes to
non-competitive antagonists. Neuroreport 1993, 4:687-690.
50. Sharp FR, Tomitaka M, Bernaudin M, Tomitaka S: Psychosis:
pathological activation of limbic thalamocortical circuits by
psychomimetics and schizophrenia? Trends Neurosci 2001,
24:330-334.
51. Sonkusare SK, Kaul CL, Ramarao P: Dementia of Alzheimer’s
disease and other neurodegenerative disorders-memantine, a
new hope. Pharmacol Res 2005, 51:1-17.
52. Rogawski MA: Low affinity channel blocking (uncompetitive)
NMDA receptor antagonists as therapeutic agents — toward
an understanding of their favorable tolerability.
Amino Acids 2000, 19:133-149.
53. Danysz W, Parsons CG: The NMDA receptor antagonist
memantine as a symptomatological and neuroprotective
treatment for Alzheimer’s disease: preclinical evidence.
Int J Geriatr Psychiatry 2003, 18:S23-S32.
www.sciencedirect.com
54. Persson J, Hasselström J, Maurset A, Öye I, Svensson J-O,
Almqvist O, Scheinin H, Gustafsson LL, Almqvist O:
Pharmacokinetics and non-analgesic effects of S- and R-
ketamine in healthy volunteers with normal and reduced
metabolic capacity. Eur J Clin Pharmacol 2002, 57:869-875.
55. Grant IS, Nimmo WS, Clements JA: Pharmacokinetics and
analgesic effects of i.m. and oral ketamine. Br J Anaesth 1981,
53:805-810.
56. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R,
Bremner JD, Heninger GR, Bowers MB, Charney DS:
Subanesthetic effects of the noncompetitive NMDA
antagonist, ketamine, in humans. Arch Gen Psychiatry 1994,
51:199-214.
57. Busto U, Bendayan R, Sellers EM: Clinical pharmacokinetics of
non-opiate abused drugs. Clin Pharmacokinetics 1989, 16:1-26.
58. Bolshakov KV, Kim KH, Potapjeva NN, Gmiro VE, Tikhonov DB,
Usherwood PN, Mellor IR, Magazanik LG: Design of antagonists
for NMDA and AMPA receptors. Neuropharmacology 2005,
49:144-155.
59. Blanpied TA, Clarke RJ, Johnson JW: Amantadine inhibits NMDA
 receptors by accelerating channel closure during channel
block. J Neurosci 2005, 25:3312-3322.
Occupation of the channel of NMDARs by the clinically useful memantine
analog amantadine is shown to cause the channel to close more quickly.
This effect of amantadine on channel gating lowers its IC50.
60. Mealing GA, Lanthorn TH, Small DL, Murray RJ, Mattes KC,
Comas TM, Morley P: Structural modifications to an
N-methyl-D-aspartate receptor antagonist result in large
differences in trapping block. J Pharmacol Exp Ther 2001,
297:906-914.
61. Sobolevsky AI, Beck C, Wollmuth LP: Molecular rearrangements
of the extracellular vestibule in NMDAR channels during
gating. Neuron 2002, 33:75-85.
62. Qian A, Johnson JW: Channel gating of NMDA receptors.
Physiol Behav 2002, 77:577-582.
Current Opinion in Pharmacology 2006, 6:61–67