NMDA receptor antagonist

Last updated

Ketamine, one of the most popular NMDA receptor antagonists. Ketamine 10ml bottle.jpg
Ketamine, one of the most popular NMDA receptor antagonists.

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 human and non-human animals; the state of anesthesia they induce is referred to as dissociative anesthesia.

Contents

Several synthetic opioids function additionally as NMDAR-antagonists, such as pethidine, levorphanol, methadone, dextropropoxyphene, tramadol, and ketobemidone.

Some NMDA receptor antagonists, such as ketamine, dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), and nitrous oxide (N2O), are sometimes used as recreational drugs, for their dissociative, hallucinogenic, and euphoriant properties. When used recreationally, they are classified as dissociative drugs.

Uses and effects

NMDA receptor antagonists induce a state called dissociative anesthesia, marked by catalepsy, amnesia, and analgesia. [1] Ketamine is a favored anesthetic for emergency patients with unknown medical history and in the treatment of burn victims because it depresses breathing and circulation less than other anesthetics. [2] [3] Dextrorphan, a metabolite of dextromethorphan (one of the most commonly used cough suppressants in the world [4] ), is known to be an NMDA receptor antagonist.

Numerous detrimental symptoms are linked to depressed NMDA receptor function. For example, NMDA receptor hypofunction that occurs as the brain ages may be partially responsible for memory deficits associated with aging. [5] Schizophrenia may also have to do with irregular NMDA receptor function (the glutamate hypothesis of schizophrenia). [6] Increased levels of another NMDA antagonist, kynurenic acid, may aggravate the symptoms of schizophrenia, according to the "kynurenic hypothesis". [7] NMDA receptor antagonists can mimic these problems; they sometimes induce "psychotomimetic" side effects, symptoms resembling psychosis. Such side effects caused by NMDA receptor inhibitors include hallucinations, paranoid delusions, confusion, difficulty concentrating, agitation, alterations in mood, nightmares, [8] catatonia, [9] ataxia, [10] anesthesia, [11] and learning and memory deficits. [12]

Because of these psychotomimetic effects, NMDA receptor antagonists, especially phencyclidine, ketamine, and dextromethorphan, are used as recreational drugs. At subanesthetic doses, these drugs have mild stimulant effects and, at higher doses, begin inducing dissociation and hallucinations, though these effects and the strength thereof vary from drug to drug. [13]

Most NMDA receptor antagonists are metabolized in the liver. [14] [15] Frequent administration of most NMDA receptor antagonists can lead to tolerance, whereby the liver will more quickly eliminate NMDA receptor antagonists from the bloodstream. [16]

NMDA receptor antagonists are also under investigation as antidepressants. Ketamine has been demonstrated to produce lasting antidepressant effects after administration in a clinical setting. In 2019, esketamine, an NMDA antagonist enantiomer of ketamine, was approved for use as an antidepressant in the United States. [17] In 2022, Auvelity was approved by the FDA for the treatment of depression.[ citation needed ] This combination medication contains dextromethorphan, an NMDA receptor antagonist.

Neurotoxicity

Olney's lesions involve mass vacuolization of neurons observed in rodents. [18] [19] However, many suggest that this is not a valid model of human use, and studies conducted on primates have shown that use must be heavy and chronic to cause neurotoxicity. [20] [21] A 2009 review found no evidence of ketamine-induced neuron death in humans. [22] However, temporary and permanent cognitive impairments have been shown to occur in long-term or heavy human users of the NMDA antagonists PCP and ketamine. A large-scale, longitudinal study found that current frequent ketamine users have modest cognitive deficits, while infrequent or former heavy users do not. [23] Many drugs have been found that lessen the risk of neurotoxicity from NMDA receptor antagonists. Centrally acting alpha 2 agonists such as clonidine and guanfacine are thought to most directly target the etiology of NMDA neurotoxicity. Other drugs acting on various neurotransmitter systems known to inhibit NMDA antagonist neurotoxicity include: anticholinergics, diazepam, barbiturates, [24] ethanol, [25] 5-HT2A serotonin receptor agonists, [26] anticonvulsants, [27] and muscimol. [28]

Potential for treatment of excess excitotoxicity

Since NMDA receptor overactivation is implicated in excitotoxicity, NMDA receptor antagonists have held much promise for the treatment of conditions that involve excitotoxicity, including benzodiazepine withdrawal, traumatic brain injury, stroke, and neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's. This is counterbalanced by the risk of developing Olney's lesions, [29] and studies have started to find agents that prevent this neurotoxicity. [25] [28] Most clinical trials involving NMDA receptor antagonists have failed due to unwanted side effects of the drugs; since the receptors also play an important role in normal glutamatergic neurotransmission, blocking them causes side-effects. These results have not yet been reproduced in humans, however. [30] Mild NMDA receptor antagonists like amitriptyline have been found to be helpful in benzodiazepine withdrawal. [31]

Mechanism of action

Simplified model of NMDAR activation and various types of NMDAR blockers. NMDA receptor activation and antagonists.PNG
Simplified model of NMDAR activation and various types of NMDAR blockers.

The NMDA receptor is an ionotropic receptor that allows for the transfer of electrical signals between neurons in the brain and in the spinal column. For electrical signals to pass, the NMDA receptor must be open. To remain open, glutamate and glycine must bind to the NMDA receptor. An NMDA receptor that has glycine and glutamate bound to it and has an open ion channel is called "activated."

Chemicals that deactivate the NMDA receptor are called antagonists. NMDAR antagonists fall into four categories: Competitive antagonists block binding to neurotransmitter glutamate sites; glycine antagonists block binding to glycine sites; noncompetitive antagonists inhibit binding to NMDARs allosteric sites; and uncompetitive antagonists block binding to a site within the ion channel. [10]

Examples

Competitive antagonists

Uncompetitive channel blockers

Non-competitive antagonists

Glycine antagonists

These drugs act at the glycine binding site:

Potencies

Uncompetitive channel blockers

Against rat NMDAR [66]
Compound IC50 (nM)Ki (nM)
(+)-MK-801 4.12.5
Chlorophenidine 14.69.3
Diphenidine 28.618.2
Methoxyphenidine 56.536.0
Phencyclidine 9157.9
Ketamine 508.5323.9
Memantine 594.2378.4

See also

Related Research Articles

<span class="mw-page-title-main">Recreational use of dextromethorphan</span> Cough suppressant drug susceptible to misuse.

Dextromethorphan, or DXM, a common active ingredient found in many over-the-counter cough suppressant cold medicines, is used as a recreational drug and entheogen for its dissociative effects. It has almost no psychoactive effects at medically recommended doses. However, dextromethorphan has powerful dissociative properties when administered in doses well above those considered therapeutic for cough suppression. Recreational use of DXM is sometimes referred to in slang form as "robo-tripping", whose prefix derives from the Robitussin brand name, or "Triple Cs", which derives from the Coricidin brand whose tablets are printed with "CC+C" for "Coricidin Cough and Cold". However, this brand presents additional danger when used at recreational doses due to the presence of chlorpheniramine.

<span class="mw-page-title-main">Ketamine</span> Dissociative anesthetic and anti-depressant

Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a treatment for depression and pain management. It is a novel compound that was derived from phencyclidine in 1962 in pursuit of a safer anesthetic with fewer hallucinogenic effects.

<span class="mw-page-title-main">Phencyclidine</span> Dissociative hallucinogenic drug, mostly used recreationally

Phencyclidine or phenylcyclohexyl piperidine (PCP), also known in its use as a street drug as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted perceptions of sounds, and violent behavior. As a recreational drug, it is typically smoked, but may be taken by mouth, snorted, or injected. It may also be mixed with cannabis or tobacco.

Dissociatives, colloquially dissos, are a subclass of hallucinogens which distort perception of sight and sound and produce feelings of detachment – dissociation – from the environment and/or self. Although many kinds of drugs are capable of such action, dissociatives are unique in that they do so in such a way that they produce hallucinogenic effects, which may include dissociation, a general decrease in sensory experience, hallucinations, dream-like states or anesthesia. Despite most dissociatives' main mechanism of action being tied to NMDA receptor antagonism, some of these substances, which are nonselective in action and affect the dopamine and/or opioid systems, may be capable of inducing more direct and repeatable euphoria or symptoms which are more akin to the effects of typical "hard drugs" or common drugs of abuse. This is likely why dissociatives are considered to be addictive with a fair to moderate potential for abuse, unlike psychedelics. Despite some dissociatives, such as phencyclidine (PCP) possessing stimulating properties, most dissociatives seem to have a general depressant effect and can produce sedation, respiratory depression, nausea, disorientation, analgesia, anesthesia, ataxia, cognitive and memory impairment as well as amnesia.

<i>N</i>-Methyl-<small>D</small>-aspartic acid Amino acid derivative

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.

<span class="mw-page-title-main">NMDA receptor</span> Glutamate receptor and ion channel protein found in nerve cells

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.

<span class="mw-page-title-main">Dizocilpine</span> Chemical compound

Dizocilpine (INN), also known as MK-801, is a pore blocker of the 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.

<span class="mw-page-title-main">Olney's lesions</span> Neurotoxicity caused by some NMDA receptor antagonists

Olney's lesions, also known as NMDA receptor antagonist neurotoxicity (NAT), is a form of brain damage consisting of selective death of neurons but not glia, observed in restricted brain regions of rats and certain other model animals exposed to large quantities of psychoactive drugs that inhibit the normal operation of the neuronal NMDA receptor. NMDA antagonism is common in anesthesia, as well as certain psychiatric treatments.

<span class="mw-page-title-main">Dextromethorphan</span> Morphinan antitussive and dissociative drug

Dextromethorphan (DXM) is a cough suppressant used in many cough and cold medicines. It affects serotonin, norepinephrine, NMDA, and sigma-1 receptors in the brain, all of which have been implicated in the pathophysiology of depression. In 2022, the FDA approved the combination dextromethorphan/bupropion to serve as a rapid acting antidepressant in patients with major depressive disorder.

<span class="mw-page-title-main">Tenocyclidine</span> Chemical compound

Tenocyclidine (TCP) is a dissociative anesthetic with psychostimulant effects. It was discovered by a team at Parke-Davis in the late 1950s. It is similar in effects to phencyclidine (PCP) but is considerably more potent. TCP has slightly different binding properties to PCP, with more affinity for the NMDA receptors, but less affinity for the sigma receptors. Because of its high affinity for the PCP site of the NMDA receptor complex, the 3H radiolabelled form of TCP is widely used in research into NMDA receptors.

<span class="mw-page-title-main">Etoxadrol</span> Chemical compound

Etoxadrol (CL-1848C) is a dissociative anaesthetic drug that has been found to be an NMDA antagonist and produce similar effects to PCP in animals. Etoxadrol, along with another related drug dexoxadrol, were developed as analgesics for use in humans, but development was discontinued in the late 1970s after patients reported side effects such as nightmares and hallucinations.

<span class="mw-page-title-main">Selfotel</span> Chemical compound

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.

Hallucinogens are a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mood, and perception as well as other changes. Most hallucinogens can be categorized as either being psychedelics, dissociatives, or deliriants.

<span class="mw-page-title-main">2-Methyl-6-(phenylethynyl)pyridine</span> Chemical compound

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.

<span class="mw-page-title-main">Arylcyclohexylamine</span> Class of chemical compounds

Arylcyclohexylamines, also known as arylcyclohexamines or arylcyclohexanamines, are a chemical class of pharmaceutical, designer, and experimental drugs.

<span class="mw-page-title-main">Traxoprodil</span> Chemical compound

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.

<span class="mw-page-title-main">HA-966</span> Chemical compound

HA-966 or (±)-3-amino-1-hydroxy-pyrrolidin-2-one is a molecule used in scientific research as a glycine receptor and NMDA receptor antagonist / low efficacy partial agonist. It has neuroprotective and anticonvulsant, anxiolytic, antinociceptive and sedative / hypnotic effects in animal models. Pilot human clinical trials in the early 1960s showed that HA-966 appeared to benefit patients with tremors of extrapyramidal origin.

<span class="mw-page-title-main">7-Chlorokynurenic acid</span> Chemical compound

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.

<span class="mw-page-title-main">3-MeO-PCMo</span> Chemical compound

3-MeO-PCMo is a dissociative anesthetic drug which is similar in structure to phencyclidine and been sold online as a designer drug. The inhibitory effect of 3-MeO-PCMo on the reduction in the density of the drebrin clusters by NMDAR stimulation with glutamic acid is lower than that of PCP or 3-MeO-PCP, with half maximal inhibitory concentration (IC50) values of 26.67 μM (3-MeO-PCMo), 2.02 μM (PCP) and 1.51 μM (3-MeO-PCP).

<span class="mw-page-title-main">PD-137889</span> Chemical compound

PD-137889 (N-methylhexahydrofluorenamine) is a chemical compound that is active as an NMDA receptor antagonist in the central nervous system at roughly 30 times the potency of the "flagship" of its class, ketamine, and substitutes for phencyclidine in animal studies. Ki [3H]TCP binding = 27 nM versus ketamine's Ki = 860 nM.

References

  1. ↑ Pender JW (February 1971). "Dissociative anesthesia". JAMA. 215 (7): 1126–30. doi:10.1001/jama.1971.03180200050011. PMC   1518731 . PMID   5107596.
  2. ↑ Ceber M, Salihoglu T (2006). "Ketamine may be the first choice for anesthesia in burn patients". Journal of Burn Care & Research. 27 (5): 760–2. doi:10.1097/01.BCR.0000238091.41737.7C. PMID   16998413.
  3. ↑ Heshmati F, Zeinali MB, Noroozinia H, Abbacivash R, Mahoori A (December 2003). "Use of ketamine in severe status asthmaticus in intensive care unit". Iranian Journal of Allergy, Asthma, and Immunology. 2 (4): 175–80. PMID   17301376.
  4. ↑ Equinozzi R, Robuschi M (2006). "Comparative efficacy and tolerability of pholcodine and dextromethorphan in the management of patients with acute, non-productive cough : a randomized, double-blind, multicenter study". Treatments in Respiratory Medicine. 5 (6): 509–13. doi:10.2165/00151829-200605060-00014. PMID   17154678. S2CID   58323644.
  5. ↑ Newcomer JW, Krystal JH (2001). "NMDA receptor regulation of memory and behavior in humans". Hippocampus. 11 (5): 529–42. doi:10.1002/hipo.1069. PMID   11732706. S2CID   32617915.
  6. ↑ Lipina T, Labrie V, Weiner I, Roder J (April 2005). "Modulators of the glycine site on NMDA receptors, D-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia". Psychopharmacology. 179 (1): 54–67. doi:10.1007/s00213-005-2210-x. PMID   15759151. S2CID   10858756.
  7. ↑ Erhardt S, Schwieler L, Nilsson L, Linderholm K, Engberg G (September 2007). "The kynurenic acid hypothesis of schizophrenia". Physiology & Behavior. 92 (1–2): 203–9. doi:10.1016/j.physbeh.2007.05.025. PMID   17573079. S2CID   46156877.
  8. ↑ Muir KW, Lees KR (March 1995). "Clinical experience with excitatory amino acid antagonist drugs". Stroke. 26 (3): 503–13. doi:10.1161/01.STR.26.3.503. PMID   7886734.
  9. ↑ Aarts MM, Tymianski M (September 2003). "Novel treatment of excitotoxicity: targeted disruption of intracellular signalling from glutamate receptors". Biochemical Pharmacology. 66 (6): 877–86. doi:10.1016/S0006-2952(03)00297-1. PMID   12963474.
  10. 1 2 3 Kim AH, Kerchner GA, Choi DW (2002). "Blocking Excitotoxicity". In Marcoux FW, Choi DW (eds.). CNS Neuroprotection. New York: Springer. pp. 3–36.
  11. ↑ Kristensen JD, Svensson B, Gordh T (November 1992). "The NMDA-receptor antagonist CPP abolishes neurogenic 'wind-up pain' after intrathecal administration in humans". Pain. 51 (2): 249–53. doi:10.1016/0304-3959(92)90266-E. PMID   1484720. S2CID   37828325.
  12. ↑ Rockstroh S, Emre M, Tarral A, Pokorny R (April 1996). "Effects of the novel NMDA-receptor antagonist SDZ EAA 494 on memory and attention in humans". Psychopharmacology. 124 (3): 261–6. doi:10.1007/BF02246666. PMID   8740048. S2CID   36727794.
  13. ↑ Lim DK (January 2003). "Ketamine associated psychedelic effects and dependence". Singapore Medical Journal. 44 (1): 31–4. PMID   12762561.
  14. ↑ Chia YY, Liu K, Chow LH, Lee TY (September 1999). "The preoperative administration of intravenous dextromethorphan reduces postoperative morphine consumption". Anesthesia and Analgesia. 89 (3): 748–52. doi: 10.1097/00000539-199909000-00041 . PMID   10475318.
  15. ↑ Kharasch ED, Labroo R (December 1992). "Metabolism of ketamine stereoisomers by human liver microsomes". Anesthesiology. 77 (6): 1201–7. doi: 10.1097/00000542-199212000-00022 . PMID   1466470.
  16. ↑ Livingston A, Waterman AE (September 1978). "The development of tolerance to ketamine in rats and the significance of hepatic metabolism". British Journal of Pharmacology. 64 (1): 63–9. doi:10.1111/j.1476-5381.1978.tb08641.x. PMC   1668251 . PMID   698482.
  17. ↑ "FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic". Food and Drug Administration . 24 March 2020.
  18. ↑ Olney JW, Labruyere J, Price MT (June 1989). "Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs". Science. 244 (4910): 1360–2. Bibcode:1989Sci...244.1360O. doi:10.1126/science.2660263. PMID   2660263.
  19. ↑ Hargreaves RJ, Hill RG, Iversen LL (1994). "Neuroprotective NMDA Antagonists: The Controversy over Their Potential for Adverse Effects on Cortical Neuronal Morphology". Brain Edema IX. Vol. 60. pp. 15–9. doi:10.1007/978-3-7091-9334-1_4. ISBN   978-3-7091-9336-5. PMID   7976530.{{cite book}}: |journal= ignored (help)
  20. ↑ Sun L, Li Q, Li Q, Zhang Y, Liu D, Jiang H, Pan F, Yew DT (March 2014). "Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys". Addiction Biology. 19 (2): 185–94. doi:10.1111/adb.12004. PMID   23145560. S2CID   23028521.
  21. ↑ Slikker W, Zou X, Hotchkiss CE, Divine RL, Sadovova N, Twaddle NC, Doerge DR, Scallet AC, Patterson TA, Hanig JP, Paule MG, Wang C (July 2007). "Ketamine-induced neuronal cell death in the perinatal rhesus monkey". Toxicological Sciences. 98 (1): 145–58. doi: 10.1093/toxsci/kfm084 . PMID   17426105.
  22. ↑ Green SM, Coté CJ (August 2009). "Ketamine and neurotoxicity: clinical perspectives and implications for emergency medicine". Annals of Emergency Medicine. 54 (2): 181–90. doi:10.1016/j.annemergmed.2008.10.003. PMID   18990467.
  23. ↑ Morgan CJ, Muetzelfeldt L, Curran HV (January 2010). "Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study". Addiction. 105 (1): 121–33. doi:10.1111/j.1360-0443.2009.02761.x. PMID   19919593.
  24. ↑ Olney JW, Labruyere J, Wang G, Wozniak DF, Price MT, Sesma MA (December 1991). "NMDA antagonist neurotoxicity: mechanism and prevention". Science. 254 (5037): 1515–8. Bibcode:1991Sci...254.1515O. doi:10.1126/science.1835799. PMID   1835799.
  25. 1 2 Farber NB, Heinkel C, Dribben WH, Nemmers B, Jiang X (November 2004). "In the adult CNS, ethanol prevents rather than produces NMDA antagonist-induced neurotoxicity". Brain Research. 1028 (1): 66–74. doi:10.1016/j.brainres.2004.08.065. PMID   15518643. S2CID   9346522.
  26. ↑ Farber NB, Hanslick J, Kirby C, McWilliams L, Olney JW (January 1998). "Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity". Neuropsychopharmacology. 18 (1): 57–62. doi: 10.1016/S0893-133X(97)00127-9 . PMID   9408919.
  27. ↑ Farber N, Jiang X, Heinkel C, Nemmers B (23 August 2002). "Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity". Molecular Psychiatry. 7 (1): 726–733. doi: 10.1038/sj.mp.4001087 . PMID   12192617.
  28. 1 2 Farber NB, Jiang X, Dikranian K, Nemmers B (December 2003). "Muscimol prevents NMDA antagonist neurotoxicity by activating GABAA receptors in several brain regions". Brain Research. 993 (1–2): 90–100. doi:10.1016/j.brainres.2003.09.002. PMID   14642834. S2CID   39247873.
  29. ↑ Maas AI (April 2001). "Neuroprotective agents in traumatic brain injury". Expert Opinion on Investigational Drugs. 10 (4): 753–67. doi:10.1517/13543784.10.4.753. PMID   11281824. S2CID   12111585.
  30. ↑ Chen HS, Lipton SA (June 2006). "The chemical biology of clinically tolerated NMDA receptor antagonists". Journal of Neurochemistry. 97 (6): 1611–26. doi: 10.1111/j.1471-4159.2006.03991.x . PMID   16805772.
  31. ↑ Gardoni F, Di Luca M (September 2006). "New targets for pharmacological intervention in the glutamatergic synapse". European Journal of Pharmacology. 545 (1): 2–10. doi:10.1016/j.ejphar.2006.06.022. PMID   16831414.
  32. ↑ Abizaid A, Liu ZW, Andrews ZB, Shanabrough M, Borok E, Elsworth JD, Roth RH, Sleeman MW, Picciotto MR, Tschöp MH, Gao XB, Horvath TL (December 2006). "Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite". The Journal of Clinical Investigation. 116 (12): 3229–39. doi:10.1172/JCI29867. PMC   1618869 . PMID   17060947.
  33. ↑ van den Bos R, Charria Ortiz GA, Cools AR (June 1992). "Injections of the NMDA-antagonist D-2-amino-7-phosphonoheptanoic acid (AP-7) into the nucleus accumbens of rats enhance switching between cue-directed behaviours in a swimming test procedure". Behavioural Brain Research. 48 (2): 165–70. doi:10.1016/S0166-4328(05)80153-6. PMID   1535501. S2CID   3997779.
  34. ↑ Fagg GE, Olpe HR, Pozza MF, Baud J, Steinmann M, Schmutz M, et al. (April 1990). "CGP 37849 and CGP 39551: novel and potent competitive N-methyl-D-aspartate receptor antagonists with oral activity". British Journal of Pharmacology. 99 (4): 791–7. doi:10.1111/j.1476-5381.1990.tb13008.x. PMC   1917531 . PMID   1972895.
  35. ↑ Eblen F, Löschmann PA, Wüllner U, Turski L, Klockgether T (March 1996). "Effects of 7-nitroindazole, NG-nitro-L-arginine, and D-CPPene on harmaline-induced postural tremor, N-methyl-D-aspartate-induced seizures, and lisuride-induced rotations in rats with nigral 6-hydroxydopamine lesions". European Journal of Pharmacology. 299 (1–3): 9–16. doi:10.1016/0014-2999(95)00795-4. PMID   8901001.
  36. ↑ "Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy", University Health Network, Toronto, September 2005
  37. ↑ "MedlinePlus Drug Information: Amantadine." MedlinePlus website Accessed 29 May 2007
  38. ↑ Ludolph AG, Udvardi PT, Schaz U, Henes C, Adolph O, Weigt HU, Fegert JM, Boeckers TM, Föhr KJ (May 2010). "Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations". British Journal of Pharmacology. 160 (2): 283–91. doi:10.1111/j.1476-5381.2010.00707.x. PMC   2874851 . PMID   20423340.
  39. 1 2 Wong BY, Coulter DA, Choi DW, Prince DA (February 1988). "Dextrorphan and dextromethorphan, common antitussives, are antiepileptic and antagonize N-methyl-D-aspartate in brain slices". Neuroscience Letters. 85 (2): 261–6. doi:10.1016/0304-3940(88)90362-X. PMID   2897648. S2CID   9903072.
  40. ↑ European Patent 0346791 1,2-Diarylethylamines for Treatment of Neurotoxic Injury.
  41. ↑ Fix AS, Horn JW, Wightman KA, Johnson CA, Long GG, Storts RW, Farber N, Wozniak DF, Olney JW (October 1993). "Neuronal vacuolization and necrosis induced by the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK(+)801 (dizocilpine maleate): a light and electron microscopic evaluation of the rat retrosplenial cortex". Experimental Neurology. 123 (2): 204–15. doi:10.1006/exnr.1993.1153. PMID   8405286. S2CID   24839154.
  42. ↑ Maxwell, Kenneth S.; Robinson, James M.; Hoffmann, Ines; Hou, Huiying J.; Searchfield, Grant; Baguley, David M.; McMurry, Gordon; Piu, Fabrice; Anderson, Jeffery J. (8 October 2021). "Intratympanic Administration of OTO-313 Reduces Tinnitus in Patients With Moderate to Severe, Persistent Tinnitus: A Phase 1/2 Study". Otology & Neurotology. Ovid Technologies (Wolters Kluwer Health). 42 (10): e1625–e1633. doi: 10.1097/mao.0000000000003369 . ISSN   1531-7129. PMC   8584222 . PMID   34629442.
  43. ↑ Harrison NL, Simmonds MA (February 1985). "Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex". British Journal of Pharmacology. 84 (2): 381–91. doi:10.1111/j.1476-5381.1985.tb12922.x. PMC   1987274 . PMID   2858237.
  44. ↑ Chawla PS, Kochar MS (May 2006). "What's new in clinical pharmacology and therapeutics". WMJ. 105 (3): 24–9. PMID   16749321.
  45. ↑ Shultz RB, Zhong Y (May 2017). "Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury". Neural Regeneration Research. 12 (5): 702–713. doi: 10.4103/1673-5374.206633 . PMC   5461601 . PMID   28616020.
  46. ↑ Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S, Dziewczapolski G, Nakamura T, Cao G, Pratt AE, Kang YJ, Tu S, Molokanova E, McKercher SR, Hires SA, Sason H, Stouffer DG, Buczynski MW, Solomon JP, Michael S, Powers ET, Kelly JW, Roberts A, Tong G, Fang-Newmeyer T, Parker J, Holland EA, Zhang D, Nakanishi N, Chen HS, Wolosker H, Wang Y, Parsons LH, Ambasudhan R, Masliah E, Heinemann SF, Piña-Crespo JC, Lipton SA (July 2013). "Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss". Proceedings of the National Academy of Sciences of the United States of America. 110 (27): E2518–27. Bibcode:2013PNAS..110E2518T. doi: 10.1073/pnas.1306832110 . PMC   3704025 . PMID   23776240.
  47. ↑ Grasshoff C, Drexler B, Rudolph U, Antkowiak B (2006). "Anaesthetic drugs: linking molecular actions to clinical effects". Current Pharmaceutical Design. 12 (28): 3665–79. doi:10.2174/138161206778522038. PMID   17073666.
  48. ↑ Ko JC, Smith TA, Kuo WC, Nicklin CF (1998). "Comparison of anesthetic and cardiorespiratory effects of diazepam-butorphanol-ketamine, acepromazine-butorphanol-ketamine, and xylazine-butorphanol-ketamine in ferrets". Journal of the American Animal Hospital Association . 34 (5): 407–16. doi:10.5326/15473317-34-5-407. PMID   9728472.
  49. ↑ Banerjee A, Schepmann D, Köhler J, Würthwein EU, Wünsch B (November 2010). "Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists". Bioorganic & Medicinal Chemistry. 18 (22): 7855–67. doi:10.1016/j.bmc.2010.09.047. PMID   20965735.
  50. ↑ Nadler V, Mechoulam R, Sokolovsky M (November 1993). "The non-psychotropic cannabinoid (+)-(3S,4S)-7-hydroxy-delta 6- tetrahydrocannabinol 1,1-dimethylheptyl (HU-211) attenuates N-methyl-D-aspartate receptor-mediated neurotoxicity in primary cultures of rat forebrain". Neuroscience Letters. 162 (1–2): 43–5. doi:10.1016/0304-3940(93)90555-Y. PMID   8121633. S2CID   34955663.
  51. ↑ Zhang JM, Hu GY (2001). "Huperzine A, a nootropic alkaloid, inhibits N-methyl-D-aspartate-induced current in rat dissociated hippocampal neurons". Neuroscience. 105 (3): 663–9. doi:10.1016/s0306-4522(01)00206-8. PMID   11516831. S2CID   25801039.
  52. ↑ Qian ZM, Ke Y (2014). "Huperzine A: Is it an Effective Disease-Modifying Drug for Alzheimer's Disease?". Frontiers in Aging Neuroscience. 6: 216. doi: 10.3389/fnagi.2014.00216 . PMC   4137276 . PMID   25191267.
  53. ↑ Coleman BR, Ratcliffe RH, Oguntayo SA, Shi X, Doctor BP, Gordon RK, Nambiar MP (September 2008). "[+]-Huperzine A treatment protects against N-methyl-D-aspartate-induced seizure/status epilepticus in rats". Chemico-Biological Interactions. 175 (1–3): 387–95. doi:10.1016/j.cbi.2008.05.023. PMID   18588864.
  54. ↑ Karlov D, Barygin O, Dron M, Palyulin V, Grigoriev V, Fedorov M (2019). "Short peptide with an inhibitory activity on the NMDA/Gly-induced currents". SAR and QSAR in Environmental Research. 30 (9): 683–695. doi:10.1080/1062936X.2019.1653965. S2CID   202879710.
  55. ↑ Popik P, Layer RT, Skolnick P (May 1994). "The putative anti-addictive drug ibogaine is a competitive inhibitor of [3H]MK-801 binding to the NMDA receptor complex". Psychopharmacology. 114 (4): 672–4. doi:10.1007/BF02245000. PMID   7531855. S2CID   8779011.
  56. ↑ Brown TK (March 2013). "Ibogaine in the treatment of substance dependence". Current Drug Abuse Reviews. 6 (1): 3–16. doi:10.2174/15672050113109990001. PMID   23627782.
  57. ↑ Muir KW (February 2006). "Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists". Current Opinion in Pharmacology. 6 (1): 53–60. doi:10.1016/j.coph.2005.12.002. PMID   16359918.
  58. ↑ Hara K, Sata T (January 2007). "Inhibitory effect of gabapentin on N-methyl-D-aspartate receptors expressed in Xenopus oocytes". Acta Anaesthesiologica Scandinavica. 51 (1): 122–8. doi:10.1111/j.1399-6576.2006.01183.x. PMID   17073851. S2CID   32385475.
  59. ↑ Hartley DM, Monyer H, Colamarino SA, Choi DW (1990). "7-Chlorokynurenate Blocks NMDA Receptor-Mediated Neurotoxicity in Murine Cortical Culture". The European Journal of Neuroscience. 2 (4): 291–295. doi:10.1111/j.1460-9568.1990.tb00420.x. PMID   12106035. S2CID   26088526.
  60. ↑ Frankiewicz T, Pilc A, Parsons CG (February 2000). "Differential effects of NMDA-receptor antagonists on long-term potentiation and hypoxic/hypoglycaemic excitotoxicity in hippocampal slices". Neuropharmacology. 39 (4): 631–42. doi:10.1016/S0028-3908(99)00168-9. PMID   10728884. S2CID   16639516.
  61. ↑ Khan MJ, Seidman MD, Quirk WS, Shivapuja BG (2000). "Effects of kynurenic acid as a glutamate receptor antagonist in the guinea pig". European Archives of Oto-Rhino-Laryngology. 257 (4): 177–81. doi:10.1007/s004050050218. PMID   10867830. S2CID   21396821.
  62. ↑ Kvist T, Steffensen TB, Greenwood JR, Mehrzad Tabrizi F, Hansen KB, Gajhede M, Pickering DS, Traynelis SF, Kastrup JS, Bräuner-Osborne H (November 2013). "Crystal structure and pharmacological characterization of a novel N-methyl-D-aspartate (NMDA) receptor antagonist at the GluN1 glycine binding site". The Journal of Biological Chemistry. 288 (46): 33124–35. doi: 10.1074/jbc.M113.480210 . PMC   3829161 . PMID   24072709.
  63. ↑ Glushakov AV, Dennis DM, Morey TE, Sumners C, Cucchiara RF, Seubert CN, Martynyuk AE (2002). "Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria". Molecular Psychiatry. 7 (4): 359–67. doi: 10.1038/sj.mp.4000976 . PMID   11986979.
  64. ↑ Glushakov AV, Glushakova O, Varshney M, Bajpai LK, Sumners C, Laipis PJ, Embury JE, Baker SP, Otero DH, Dennis DM, Seubert CN, Martynyuk AE (February 2005). "Long-term changes in glutamatergic synaptic transmission in phenylketonuria". Brain. 128 (Pt 2): 300–7. doi: 10.1093/brain/awh354 . PMID   15634735.
  65. ↑ Banks P, Franks NP, Dickinson R (March 2010). "Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor mediates xenon neuroprotection against hypoxia-ischemia". Anesthesiology. 112 (3): 614–22. doi: 10.1097/ALN.0b013e3181cea398 . PMID   20124979.
  66. ↑ Wallach J, Kang H, Colestock T, Morris H, Bortolotto ZA, Collingridge GL, Lodge D, Halberstadt AL, Brandt SD, Adejare A (2016). "Pharmacological Investigations of the Dissociative 'Legal Highs' Diphenidine, Methoxphenidine and Analogues". PLOS ONE. 11 (6): e0157021. Bibcode:2016PLoSO..1157021W. doi: 10.1371/journal.pone.0157021 . PMC   4912077 . PMID   27314670.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.