Editing NMDA receptor (section)

== Mechanism of action ==
NMDA receptors are a crucial part of the development of the central nervous system. The processes of learning, memory, and [[neuroplasticity]] rely on the mechanism of NMDA receptors. NMDA receptors are glutamate-gated cation channels that allow for an increase of calcium [[Permeability (Earth sciences)|permeability]]. Channel activation of NMDA receptors is a result of the binding of two co agonists, [[glycine]] and [[glutamate]].

Overactivation of NMDA receptors, causing excessive influx of Ca<sup>2+</sup> can lead to excitotoxicity. Excitotoxicity is implied to be involved in some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.<ref name="Chen" /><ref name="Kemp" /><ref name="Lipton1" /><ref name="Koch" /> Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases.<ref name="Chen" /><ref name="Kemp" /><ref name="Lipton1" /> It is, however, important to preserve physiological NMDA receptor activity while trying to block its excessive, excitotoxic activity. This can possibly be achieved by uncompetitive antagonists, blocking the receptors ion channel when excessively open.<ref name="Lipton1" />

Uncompetitive NMDA receptor antagonists, or channel blockers, enter the channel of the NMDA receptor after it has been activated and thereby block the flow of ions.<ref name="Johnson" /><ref name="Chen" /> [[MK-801]], [[ketamine]], [[amantadine]] and [[memantine]] are examples of such antagonists,<ref name="Johnson" /> see figure 1. The off-rate of an antagonist from the receptors channel is an important factor as too slow off-rate can interfere with normal function of the receptor and too fast off-rate may give ineffective blockade of an excessively open receptor.<ref name="Lipton1" />

[[Memantine]] is an example of an uncompetitive channel blocker of the NMDA receptor, with a relatively rapid off-rate and low affinity. At physiological pH its amine group is positively charged and its receptor antagonism is voltage-dependent.<ref name="Lipton1" /> It thereby mimics the physiological function of Mg<sup>2+</sup> as channel blocker.<ref name="Dominguez" /> Memantine only blocks NMDA receptor associated channels during prolonged activation of the receptor, as it occurs under excitotoxic conditions, by replacing magnesium at the binding site. During normal receptor activity the channels only stay open for several milliseconds and under those circumstances memantine is unable to bind within the channels and therefore does not interfere with normal synaptic activity.<ref name="Lipton2" />