Editing NMDA receptor (section)

== History ==
The discovery of NMDA receptors was followed by the synthesis and study of ''N''-methyl-<small>D</small>-aspartic acid (NMDA) in the 1960s by [[Jeff Watkins]] and colleagues. In the early 1980s, NMDA receptors were shown to be involved in several central synaptic pathways.<ref name="Cheng">{{cite journal | vauthors = Yamakura T, Shimoji K | title = Subunit- and site-specific pharmacology of the NMDA receptor channel | journal = Progress in Neurobiology | volume = 59 | issue = 3 | pages = 279–298 | date = October 1999 | pmid = 10465381 | doi = 10.1016/S0301-0082(99)00007-6 | s2cid = 24726102 }}</ref><ref name="Watkins">{{cite journal | vauthors = Watkins JC, Jane DE | title = The glutamate story | journal = British Journal of Pharmacology | volume = 147 | issue = S1 | pages = S100–S108 | date = January 2006 | pmid = 16402093 | pmc = 1760733 | doi = 10.1038/sj.bjp.0706444 }}</ref> Receptor subunit selectivity was discovered in the early 1990s, which led to recognition of a new class of compounds that selectively inhibit the [[NR2B]] subunit. These findings led to vigorous campaign in the pharmaceutical industry.<ref name="pmid17088105"/> From this it was considered that NMDA receptors were associated with a variety of [[neurological disorders]] such as [[epilepsy]], [[Parkinson's disease|Parkinson's]], [[Alzheimer's disease|Alzheimer's]], [[Huntington's disease|Huntington's]] and other CNS disorders.<ref name="pmid10049997"/>

In 2002, it was discovered by [[Hilmar Bading]] and co-workers that the cellular consequences of NMDA receptor stimulation depend on the receptor's location on the neuronal cell surface.<ref name="pmid11953750">{{cite journal | vauthors = Hardingham GE, Fukunaga Y, Bading H | title = Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways | journal = Nature Neuroscience | volume = 5 | issue = 5 | pages = 405–414 | date = May 2002 | pmid = 11953750 | doi = 10.1038/nn835 | s2cid = 659716 }}</ref><ref name=":4">{{cite journal | vauthors = Hardingham GE, Bading H | title = Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders | journal = Nature Reviews. Neuroscience | volume = 11 | issue = 10 | pages = 682–696 | date = October 2010 | pmid = 20842175 | pmc = 2948541 | doi = 10.1038/nrn2911 }}</ref> Synaptic NMDA receptors promote gene expression, plasticity-related events, and acquired [[neuroprotection]]. Extrasynaptic NMDA receptors promote death signaling; they cause transcriptional shut-off, mitochondrial dysfunction, and structural disintegration.<ref name="pmid11953750"/><ref name=":4" /> This pathological triad of extrasynaptic NMDA receptor signaling represents a common conversion point in the etiology of several acute and chronic neurodegenerative conditions.<ref>{{cite journal | vauthors = Bading H | title = Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations | journal = The Journal of Experimental Medicine | volume = 214 | issue = 3 | pages = 569–578 | date = March 2017 | pmid = 28209726 | pmc = 5339681 | doi = 10.1084/jem.20161673 }}</ref> The molecular basis for toxic extrasynaptic NMDA receptor signaling was uncovered by Hilmar Bading and co-workers in 2020.<ref name=":5">{{cite journal | vauthors = Yan J, Bengtson CP, Buchthal B, Hagenston AM, Bading H | title = Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants | journal = Science | volume = 370 | issue = 6513 | pages = eaay3302 | date = October 2020 | pmid = 33033186 | doi = 10.1126/science.aay3302 | s2cid = 222210921 }}</ref> [[Extrasynaptic NMDA receptors]] form a death signaling complex with TRPM4. NMDAR/TRPM4 interaction interface inhibitors (also known as interface inhibitors) disrupt the NMDAR/TRPM4 complex and detoxify extrasynaptic NMDA receptors.<ref name=":5" />

A fortuitous finding was made in 1968 when a woman was taking [[amantadine]] as flu medicine and experienced remarkable remission of her Parkinson's symptoms. This finding, reported by Scawab et al., was the beginning of [[medicinal chemistry]] of adamantane derivatives in the context of diseases affecting the CNS.<ref name="Wanka">{{cite journal | vauthors = Wanka L, Iqbal K, Schreiner PR | title = The lipophilic bullet hits the targets: medicinal chemistry of adamantane derivatives | journal = Chemical Reviews | volume = 113 | issue = 5 | pages = 3516–3604 | date = May 2013 | pmid = 23432396 | pmc = 3650105 | doi = 10.1021/cr100264t }}</ref> Before this finding, memantine, another adamantane derivative, had been synthesized by Eli Lilly and Company in 1963. The purpose was to develop a [[hypoglycemic]] drug, but it showed no such [[efficacy]]. It was not until 1972 that a possible therapeutic importance of memantine for treating neurodegenerative disorders was discovered. From 1989 memantine has been recognized to be an uncompetitive antagonist of the NMDA receptor.<ref name="Dominguez" />