Editing NMDA receptor (section)

===Agonists===
[[Image:L-Glutaminsäure - L-Glutamic_acid.svg|thumb|right|200px|<small>L</small>-[[Glutamic acid]] (glutamate), the major endogenous agonist of the main site of the NMDAR]]
[[Image:Glycine-2D-skeletal.svg|thumb|right|150px|[[Glycine]], the major endogenous agonist of the glycine co-agonist site of the NMDAR]]

Activation of NMDA receptors requires binding of [[glutamic acid|glutamate]] or [[aspartic acid|aspartate]] (aspartate does not stimulate the receptors as strongly).<ref name="pmid15703381">{{cite journal | vauthors = Chen PE, Geballe MT, Stansfeld PJ, Johnston AR, Yuan H, Jacob AL, Snyder JP, Traynelis SF, Wyllie DJ | display-authors = 6 | title = Structural features of the glutamate binding site in recombinant NR1/NR2A N-methyl-D-aspartate receptors determined by site-directed mutagenesis and molecular modeling | journal = Molecular Pharmacology | volume = 67 | issue = 5 | pages = 1470–1484 | date = May 2005 | pmid = 15703381 | doi = 10.1124/mol.104.008185 | s2cid = 13505187 }}</ref> In addition, NMDARs also require the binding of the [[co-agonist]] [[glycine]] for the efficient opening of the ion channel, which is a part of this receptor.

[[D-Serine|<small>D</small>-Serine]] has also been found to co-agonize the NMDA receptor with even greater potency than glycine.<ref name="pmid17033043">{{cite journal | vauthors = Wolosker H | title = D-serine regulation of NMDA receptor activity | journal = Science's STKE | volume = 2006 | issue = 356 | pages = pe41 | date = October 2006 | pmid = 17033043 | doi = 10.1126/stke.3562006pe41 | s2cid = 39125762 }}</ref> It is produced by [[serine racemase]], and is enriched in the same areas as NMDA receptors. Removal of <small>D</small>-serine can block NMDA-mediated excitatory neurotransmission in many areas. Recently, it has been shown that <small>D</small>-serine can be released both by neurons and astrocytes to regulate NMDA receptors. Note that D-serine has also been shown to work as an antagonist / inverse co-agonist for ''t''-NMDA receptors.<ref name=":6">{{cite journal | vauthors = Beesley S, Kumar SS | title = The t-N-methyl-d-aspartate receptor: Making the case for d-Serine to be considered its inverse co-agonist | journal = Neuropharmacology | volume = 238 | pages = 109654 | date = November 2023 | pmid = 37437688 | doi = 10.1016/j.neuropharm.2023.109654 | doi-access = free }}</ref><ref name=":3" />

NMDA receptor (NMDAR)-mediated currents are directly related to membrane depolarization. NMDA agonists therefore exhibit fast [[Mg ion (physiology)|Mg<sup>2+</sup>]] unbinding kinetics, increasing channel open probability with depolarization. This property is fundamental to the role of the NMDA receptor in [[memory]] and [[learning]], and it has been suggested that this channel is a biochemical substrate of [[Hebbian learning]], where it can act as a coincidence detector for membrane depolarization and synaptic transmission.

====Examples====
Some known NMDA receptor agonists include:
* [[Amino acid]]s and amino acid derivatives
** [[Aspartic acid]] (aspartate) ([[aspartic acid|<small>D</small>-aspartic acid]], [[aspartic acid|<small>L</small>-aspartic acid]]) – endogenous glutamate site agonist. The word ''N''-methyl-<small>D</small>-aspartate (NMDA) is partially derived from <small>D</small>-aspartate.
** [[Glutamic acid]] (glutamate) – endogenous glutamate site agonist
*** [[Tetrazolylglycine]] – synthetic glutamate site agonist
*** [[Homocysteic acid]] – endogenous glutamate site agonist
*** [[Ibotenic acid]] – naturally occurring glutamate site agonist found in ''[[Amanita muscaria]]''
*** [[Quinolinic acid]] (quinolinate) – endogenous glutamate site agonist
** [[Glycine]] – endogenous glycine site agonist
*** [[Alanine]] ([[alanine|<small>D</small>-alanine]], [[alanine|<small>L</small>-alanine]]) – endogenous glycine site agonist
*** [[Milacemide]] – synthetic glycine site agonist; prodrug of [[glycine]]
*** [[Sarcosine]] (monomethylglycine) – endogenous glycine site agonist
*** [[Serine]] ([[serine|<small>D</small>-serine]], [[serine|<small>L</small>-serine]]) – endogenous glycine site agonist
* [[Positive allosteric modulator]]s
** [[Cerebrosterol]] – endogenous weak positive allosteric modulator
** [[Cholesterol]] – endogenous weak positive allosteric modulator
** [[Dehydroepiandrosterone]] (DHEA) – endogenous weak positive allosteric modulator
** [[Dehydroepiandrosterone sulfate]] (DHEA-S) – endogenous weak positive allosteric modulator
** [[Nebostinel]] (neboglamine) – synthetic positive allosteric modulator of the glycine site
** [[Pregnenolone sulfate]] – endogenous weak positive allosteric modulator
* Polyamines
** [[Spermidine]] – endogenous polyamine site agonist
** [[Spermine]] – endogenous polyamine site agonist

==== Neramexane ====
[[File:Neramexane.svg|thumb|right|'''Figure 6:''' Chemical structure of neramexane, second generation memantine derivative]]
An example of memantine derivative is [[neramexane]] which was discovered by studying number of aminoalkyl [[cyclohexanes]], with memantine as the template, as NMDA receptor antagonists. Neramexane binds to the same site as memantine within the NMDA receptor associated channel and with comparable affinity. It does also show very similar bioavailability and blocking kinetics [[in vivo]] as memantine. Neramexane went to [[clinical trials]] for four indications, including Alzheimer's disease.<ref name="Wanka" />