Glutamatergic (NMDA receptor)

A dysfunction of glutamatergic neurotransmission, manifested as neuronal excitotoxicity, is

hypothesized to be involved in the etiology of Alzheimer's disease. Targeting the glutamatergic
system, specifically NMDA receptors, offers a novel approach to treatment in view of the
limited efficacy of existing drugs targeting the cholinergic system.[11]

Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic

NMDA receptors.[12][13] By binding to the NMDA receptor with a higher affinity than Mg2+
ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, particularly from
extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. The low affinity,
uncompetitive nature, and rapid off-rate kinetics of memantine at the level of the NMDA
receptor-channel, however, preserves the function of the receptor at synapses, as it can still be
activated by physiological release of glutamate following depolarization of the postsynaptic
neuron.[14][15][16] The interaction of memantine with NMDA receptors plays a major role in
the symptomatic improvement that the drug produces in Alzheimer's disease. However, there
is no evidence as yet that the ability of memantine to protect against NMDA receptor-
mediated excitotoxicity has a disease-modifying effect in Alzheimer's, although this has been
suggested in animal models.[15]

Serotonergic (5-HT3 receptor)

Memantine acts as a non-competitive antagonist at the 5-HT3 receptor, with a potency similar
to that for the NMDA receptor.[17] Many 5-HT3 antagonists function as antiemetics, however
the clinical significance of this serotonergic activity in the treatment of Alzheimer's disease is
unknown.

Cholinergic (nicotinic acetylcholine receptor)

Memantine acts as a non-competitive antagonist at different neuronal nicotinic acetylcholine

receptors (nAChRs) at potencies possibly similar to the NMDA and 5-HT3 receptors, but this is
difficult to ascertain with accuracy because of the rapid desensitization of nAChR responses in
these experiments. It can be noted that memantine is an antagonist at Alpha-7 nAChR, which
may contribute to initial worsening of cognitive function during early memantine treatment.
Alpha-7 nAChR upregulates quickly in response to antagonism, which could explain the
cognitive-enhancing effects of chronic memantine treatment.[18][19] It has been shown that
the number of nicotinic receptors in the brain are reduced in Alzheimer's disease, even in the
absence of a general decrease in the number of neurons, and nicotinic receptor agonists are
viewed as interesting targets for anti-Alzheimer drugs.[20]
Dopaminergic (D2 receptor)

Memantine acts as an agonist at the dopamine D2 receptor with equal or slightly higher
affinity than to the NMDA receptors.[21]

Sigmaergic (σ1 receptor)

It acts as an agonist at the σ1 receptor with a low Ki of 2.6 µM (2600 nM).[22] The
consequences of this activity are unclear (as the role of sigma receptors in general is not yet
that well understood). Due to this low affinity, therapeutic concentrations of memantine likely
are too low to have any sigmaergic effect. However, excessive doses of memantine for
recreational purposes may indeed activate this receptor.[23]