''N''-methyl--aspartic acid or ''N''-methyl--aspartate (NMDA) is an
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
derivative that acts as a specific
agonist at the
NMDA receptor mimicking the action of
glutamate, the
neurotransmitter which normally acts at that receptor. Unlike glutamate, NMDA only binds to and regulates the NMDA receptor and has no effect on other glutamate receptors (such as those for
AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, better known as AMPA, is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate.
There are several types of glutamatergic ...
and
kainate
Kainic acid, or kainate, is an acid that naturally occurs in some seaweed. Kainic acid is a potent neuroexcitatory amino acid agonist that acts by activating receptors for glutamate, the principal excitatory neurotransmitter in the central nervo ...
). NMDA receptors are particularly important when they become overactive during, for example,
withdrawal from
alcohol as this causes symptoms such as
agitation and, sometimes, epileptiform
seizures
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...
.
Biological function
In 1962, J.C. Watkins reported synthesizing NMDA, an
isomer of the previously know
''N''-Methyl--aspartic-acid (PubChem ID 4376) NMDA is a water-soluble -alpha-amino acid — an
aspartic acid derivative with an ''N''-methyl substituent and -
configuration — found across
Animalia from
lancelet
The lancelets ( or ), also known as amphioxi (singular: amphioxus ), consist of some 30 to 35 species of "fish-like" benthic filter feeding chordates in the order Amphioxiformes. They are the modern representatives of the subphylum Cephalochord ...
s to
mammals. At homeostatic levels NMDA plays an essential role as a neurotransmitter and neuroendocrine regulator. At increased but sub–toxic levels NMDA becomes neuro-protective. In excessive amounts NMDA is an excitotoxin. Behavioral neuroscience research utilizes NMDA
excitotoxicity
In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate ...
to induce lesions in specific regions of an
animal
Animals are multicellular, eukaryotic organisms in the Kingdom (biology), biological kingdom Animalia. With few exceptions, animals Heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, are Motilit ...
subject's brain or spinal cord to study behavioral changes.
The mechanism of action for the
NMDA receptor is a specific agonist binding to its NR2 subunits, and then a non-specific cation channel is opened, which can allow the passage of Ca
2+ and Na
+ into the cell and K
+ out of the cell. Therefore, NMDA receptors will only open if glutamate is in the synapse and concurrently the postsynaptic membrane is already depolarized - acting as
coincidence detectors at the neuronal level. The
excitatory postsynaptic potential
In neuroscience, an excitatory postsynaptic potential (EPSP) is a postsynaptic potential that makes the postsynaptic neuron more likely to fire an action potential. This temporary depolarization of postsynaptic membrane potential, caused by the ...
(EPSP) produced by activation of an NMDA receptor also increases the concentration of Ca
2+ in the cell. The Ca
2+ can in turn function as a second messenger in various signaling pathways. This process is modulated by a number of endogenous and exogenous compounds and plays a key role in a wide range of physiological (such as memory) and pathological processes (such as
excitotoxicity
In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate ...
).
Antagonists
Examples of
antagonists
An antagonist is a character in a story who is presented as the chief foe of the protagonist.
Etymology
The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, ri ...
, or more appropriately named receptor channel blockers, of the NMDA receptor are
APV,
amantadine
Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended due to wi ...
,
dextromethorphan
Dextromethorphan (DXM) is a medication most often used as a cough suppressant in over-the-counter cold and cough medicines. It is sold in syrup, tablet, spray, and lozenge forms. In 2022, the FDA approved a formulation of it combined with bu ...
(DXM),
ketamine
Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ...
, magnesium,
tiletamine
Tiletamine is a dissociative anesthetic and pharmacology, pharmacologically classified as an NMDA receptor antagonist. It is related chemically to ketamine. Tiletamine hydrochloride exists as odorless white crystals.
It is used in veterinary me ...
,
phencyclidine
Phencyclidine or phenylcyclohexyl piperidine (PCP), also known as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted percept ...
(PCP),
riluzole,
memantine
Memantine is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth.
Common side effects include headache, constipation, sleepiness, and dizziness. Severe side effects may include blood clots ...
,
methoxetamine
Methoxetamine, abbreviated as MXE, is a dissociative hallucinogen that has been sold as a designer drug. It differs from many dissociatives such as ketamine and phencyclidine (PCP) that were developed as pharmaceutical drugs for use as general ...
(MXE),
methoxphenidine
Methoxphenidine (methoxydiphenidine, 2-MeO-Diphenidine, MXP) is a dissociative of the diarylethylamine class that has been sold online as a designer drug. Methoxphenidine was first reported in a 1989 patent where it was tested as a treatment for ...
(MXP) and
kynurenic acid
Kynurenic acid (KYNA or KYN) is a product of the normal metabolism of amino acid -tryptophan. It has been shown that kynurenic acid possesses neuroactive activity. It acts as an antiexcitotoxic and anticonvulsant, most likely through acting as an ...
. While
dizocilpine is generally considered to be the prototypical NMDA receptor blocker and is the most common agent used in research, animal studies have demonstrated some amount of
neurotoxicity
Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...
, which may or may not also occur in humans. These compounds are commonly referred to as
NMDA receptor antagonist
NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor ( NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce ...
s.
See also
*
Anti-NMDA-receptor encephalitis
References
Further reading
*
*
{{DEFAULTSORT:Methyl-D-Aspartic Acid, N-
Neurotransmitters
Dicarboxylic acids
Amino acid derivatives
Glutamate (neurotransmitter)
Secondary amino acids