N-methyl-D-aspartic acid or N-methyl-D-aspartate (NMDA) is an amino acid 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. 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.
The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.
AP5 is a chemical compound used as a biochemical tool to study various cellular processes. It is a selective NMDA receptor antagonist that competitively inhibits the ligand (glutamate) binding site of NMDA receptors. AP5 blocks NMDA receptors in micromolar concentrations.
Dizocilpine (INN), also known as MK-801, is a pore blocker of the N-Methyl-D-aspartate (NMDA) receptor, a glutamate receptor, discovered by a team at Merck in 1982. Glutamate is the brain's primary excitatory neurotransmitter. The channel is normally blocked with a magnesium ion and requires depolarization of the neuron to remove the magnesium and allow the glutamate to open the channel, causing an influx of calcium, which then leads to subsequent depolarization. Dizocilpine binds inside the ion channel of the receptor at several of PCP's binding sites thus preventing the flow of ions, including calcium (Ca2+), through the channel. Dizocilpine blocks NMDA receptors in a use- and voltage-dependent manner, since the channel must open for the drug to bind inside it. The drug acts as a potent anti-convulsant and probably has dissociative anesthetic properties, but it is not used clinically for this purpose because of the discovery of brain lesions, called Olney's lesions (see below), in laboratory rats. Dizocilpine is also associated with a number of negative side effects, including cognitive disruption and psychotic-spectrum reactions. It inhibits the induction of long term potentiation and has been found to impair the acquisition of difficult, but not easy, learning tasks in rats and primates. Because of these effects of dizocilpine, the NMDA receptor pore blocker ketamine is used instead as a dissociative anesthetic in human medical procedures. While ketamine may also trigger temporary psychosis in certain individuals, its short half-life and lower potency make it a much safer clinical option. However, dizocilpine is the most frequently used uncompetitive NMDA receptor antagonist in animal models to mimic psychosis for experimental purposes.
CNQX or cyanquixaline (6-cyano-7-nitroquinoxaline-2,3-dione) is a competitive AMPA/kainate receptor antagonist. Its chemical formula is C9H4N4O4. CNQX is often used in the retina to block the responses of OFF-bipolar cells for electrophysiology recordings.
The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatory neurotransmitter.
Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.
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 is referred to as dissociative anesthesia.
Ifenprodil is an inhibitor of the NMDA receptor, specifically of GluN1 and GluN2B subunits. Additionally, ifenprodil inhibits GIRK channels, and interacts with alpha1 adrenergic, serotonin, and sigma receptors.
Glutamate [NMDA] receptor subunit epsilon-2, also known as N-methyl D-aspartate receptor subtype 2B, is a protein that in humans is encoded by the GRIN2B gene.
Glutamate [NMDA] receptor subunit epsilon-1 is a protein that in humans is encoded by the GRIN2A gene. With 1464 amino acids, the canonical GluN2A subunit isoform is large. GluN2A-short isoforms specific to primates can be produced by alternative splicing and contain 1281 amino acids.
Glutamate [NMDA] receptor subunit zeta-1 is a protein that in humans is encoded by the GRIN1 gene.
Midafotel is a potent, competitive antagonist at the NMDA receptor. It was originally designed as a potential therapy for excitotoxicity, epilepsy or neuropathic pain. It looked very promising in in vitro trials proving to be a potent competitive antagonist at the NMDA without affecting other receptors. Research continued through to in vivo cat studies where it proved to limit damage after occluding the middle cerebral artery, leading to ischaemia. It also blocked photosensitive epilepsies in baboons.
Tezampanel is a drug originally developed by Eli Lilly which acts as a competitive antagonist of the AMPA and kainate subtypes of the ionotropic glutamate receptor family, with selectivity for the GluR5 subtype of the kainate receptor. It has neuroprotective and anticonvulsant properties, the former of which may, at least in part, occur via blockade of calcium uptake into neurons.
Selfotel (CGS-19755) is a drug which acts as a competitive NMDA antagonist, directly competing with glutamate for binding to the receptor. Initial studies showed it to have anticonvulsant, anxiolytic, analgesic and neuroprotective effects, and it was originally researched for the treatment of stroke, but subsequent animal and human studies showed phencyclidine-like effects, as well as limited efficacy and evidence for possible neurotoxicity under some conditions, and so clinical development was ultimately discontinued.
2-Methyl-6-(phenylethynyl)pyridine (MPEP) is a research drug which was one of the first compounds found to act as a selective antagonist for the metabotropic glutamate receptor subtype mGluR5. After being originally patented as a liquid crystal for LCDs, it was developed by the pharmaceutical company Novartis in the late 1990s. It was found to produce neuroprotective effects following acute brain injury in animal studies, although it was unclear whether these results were purely from mGluR5 blockade as it also acts as a weak NMDA antagonist, and as a positive allosteric modulator of another subtype mGlu4, and there is also evidence for a functional interaction between mGluR5 and NMDA receptors in the same populations of neurons. It was also shown to produce antidepressant and anxiolytic effects in animals, and to reduce the effects of morphine withdrawal, most likely due to direct interaction between mGluR5 and the μ-opioid receptor.
Traxoprodil is a drug developed by Pfizer which acts as an NMDA antagonist, selective for the NR2B subunit. It has neuroprotective, analgesic, and anti-Parkinsonian effects in animal studies. Traxoprodil has been researched in humans as a potential treatment to lessen the damage to the brain after stroke, but results from clinical trials showed only modest benefit. The drug was found to cause EKG abnormalities and its clinical development was stopped. More recent animal studies have suggested traxoprodil may exhibit rapid-acting antidepressant effects similar to those of ketamine, although there is some evidence for similar psychoactive side effects and abuse potential at higher doses, which might limit clinical acceptance of traxoprodil for this application.
Conantokins are a small family of helical peptides that are derived from the venom of predatory marine snails of the genus Conus. Conantokins act as potent and specific antagonists of the N-methyl-D-aspartate receptor (NMDAR). They are the only naturally-derived peptides to do so. The subtypes of conantokins exhibit a surprising variability of selectivity across the NMDAR subunits, and are therefore uniquely useful in developing subunit-specific pharmacological probes.
7-Chlorokynurenic acid (7-CKA) is a tool compound that acts as a potent and selective competitive antagonist of the glycine site of the NMDA receptor. It produces ketamine-like rapid antidepressant effects in animal models of depression. However, 7-CKA is unable to cross the blood-brain-barrier, and for this reason, is unsuitable for clinical use. As a result, a centrally-penetrant prodrug of 7-CKA, 4-chlorokynurenine (AV-101), has been developed for use in humans, and is being studied in clinical trials as a potential treatment for major depressive disorder, and anti-nociception. In addition to antagonizing the NMDA receptor, 7-CKA also acts as a potent inhibitor of the reuptake of glutamate into synaptic vesicles, an action that it mediates via competitive blockade of vesicular glutamate transporters.
Rislenemdaz is an orally-active, selective NMDA receptor subunit 2B (NR2B) antagonist which is under development by Cerecor in the United States as an adjunctive therapy for treatment-resistant depression (TRD). In November 2013, phase II clinical trials were initiated, and in the same month, rislenemdaz received Fast Track Designation from the Food and Drug Administration for TRD.
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