Editing NMDA receptor (section)

=== Development of NMDA receptor antagonists ===
The main problem with the development of NMDA antagonists for neuroprotection is that physiological NMDA receptor activity is essential for normal neuronal function. Complete blockade of all NMDA receptor activity results in side effects such as [[hallucinations]], agitation and [[anesthesia]]. To be clinically relevant, an NMDA receptor antagonist must limit its action to blockade of excessive activation, without limiting normal function of the receptor.<ref name="Lipton2" />

==== Competitive NMDA receptor antagonists ====
[[Competitive]] NMDA receptor antagonists, which were developed first, are not a good option because they compete and bind to the same site (NR2 subunit) on the receptor as the agonist, glutamate, and therefore block normal function also.<ref name="Lipton2" /><ref name="Monaghan">{{cite book| vauthors = Monaghan DT, Jane DE | veditors = Van Dongen AM |title=Biology of the NMDA Receptor|date=2009|publisher=CRC Press|location=Boca Raton, Florida|isbn=978-1-4200-4414-0|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK5282/|chapter=Pharmacology of NMDA Receptors| series = Frontiers in Neuroscience |pmid=21204415}}</ref> They will block healthy areas of the brain prior to having an impact on pathological areas, because healthy areas contain lower levels of [[agonist]] than pathological areas. These antagonists can be displaced from the receptor by high concentration of glutamate which can exist under excitotoxic circumstances.<ref name="Chen" />

==== Noncompetitive NMDA receptor antagonists ====
[[File:NMDA receptor antagonist.jpg|thumb|right|200px|'''Figure 4:''' The chemical structures of MK-801, phencyclidine and ketamine, high affinity uncompetitive NMDA receptor antagonists]]
Uncompetitive NMDA receptor antagonists block within the ion channel at the Mg<sup>2+</sup> site (pore region) and prevent excessive influx of Ca<sup>2+</sup>. Noncompetitive antagonism refers to a type of block that an increased concentration of glutamate cannot overcome, and is dependent upon prior activation of the receptor by the agonist, i.e. it only enters the channel when it is opened by agonist.<ref name="Lipton2" /><ref name="Sonkusare">{{cite journal | vauthors = Sonkusare SK, Kaul CL, Ramarao P | title = Dementia of Alzheimer's disease and other neurodegenerative disorders--memantine, a new hope | journal = Pharmacological Research | volume = 51 | issue = 1 | pages = 1–17 | date = January 2005 | pmid = 15519530 | doi = 10.1016/j.phrs.2004.05.005 }}</ref>

==== Memantine and related compounds ====
[[File:Memantine and amantadine.jpg|thumb|right|300px|'''Figure 5:''' Chemical structures of memantine (right) and amantadine (left)]]
Because of these adverse side effects of high affinity blockers, the search for clinically successful NMDA receptor antagonists for neurodegenerative diseases continued and focused on developing low affinity blockers. However the affinity could not be too low and dwell time not too short (as seen with Mg<sup>2+</sup>) where membrane depolarization relieves the block. The discovery was thereby development of uncompetitive antagonist with longer dwell time than Mg<sup>2+</sup> in the channel but shorter than MK-801. That way the drug obtained would only block excessively open NMDA receptor associated channels but not normal neurotransmission.<ref name="Lipton2" /><ref name="Sonkusare" /> Memantine is that drug. It is a derivative of amantadine which was first an anti-influenza agent but was later discovered by coincidence to have efficacy in Parkinson's disease. Chemical structures of memantine and amantadine can be seen in figure 5. The compound was first thought to be [[dopaminergic]] or [[anticholinergic]] but was later found to be an NMDA receptor antagonist.<ref name="Dominguez" /><ref name="Lipton2" />

Memantine is the first drug approved for treatment of severe and more advanced [[Alzheimer's disease]], which for example anticholinergic drugs do not do much good for.<ref name="Sonkusare" /> It helps recovery of synaptic function and in that way improves impaired memory and learning.<ref name="Koch" /> In 2015 memantine is also in trials for therapeutic importance in additional neurological disorders.<ref name="Lipton3">{{cite journal | vauthors = Lipton SA | title = Pathologically activated therapeutics for neuroprotection | journal = Nature Reviews. Neuroscience | volume = 8 | issue = 10 | pages = 803–808 | date = October 2007 | pmid = 17882256 | doi = 10.1038/nrn2229 | s2cid = 34931289 }}</ref>

Many second-generation memantine derivatives have been in development that may show even better neuroprotective effects, where the main thought is to use other safe but effective modulatory sites on the NMDA receptor in addition to its associated ion channel.<ref name="Lipton3" />