Traxoprodil

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Traxoprodil
Traxoprodil.svg
Clinical data
Other namesCP-101606
ATC code
  • None
Identifiers
  • (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.222.813 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H25NO3
Molar mass 327.424 g·mol−1
3D model (JSmol)
  • c2cc(O)ccc2C(O)C(C)N3CCC(O)(CC3)c1ccccc1
  • InChI=1S/C20H25NO3/c1-15(19(23)16-7-9-18(22)10-8-16)21-13-11-20(24,12-14-21)17-5-3-2-4-6-17/h2-10,15,19,22-24H,11-14H2,1H3/t15-,19+/m0/s1 Yes check.svgY
  • Key:QEMSVZNTSXPFJA-HNAYVOBHSA-N Yes check.svgY
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Traxoprodil (developmental code name CP-101606) is a drug developed by Pfizer which acts as an NMDA antagonist, selective for the NR2B subunit. [1] [2] It has neuroprotective, [3] analgesic, [4] and anti-Parkinsonian effects in animal studies. [5] [6] Traxoprodil has been researched in humans as a potential treatment to lessen the damage to the brain after stroke, [7] [8] [9] [10] but results from clinical trials showed only modest benefit. [11] The drug was found to cause EKG abnormalities (QT prolongation) and its clinical development was stopped. [12] More recent animal studies have suggested traxoprodil may exhibit rapid-acting antidepressant effects similar to those of ketamine, [13] although there is some evidence for similar psychoactive side effects and abuse potential at higher doses, [14] which might limit clinical acceptance of traxoprodil for this application.

Traxoprodil showed ketamine-like rapidly-acting antidepressant effects in a small clinical trial of 30 patients with depression who were non-responders to 6 weeks of paroxetine treatment. [15] The response rate was 60%, relative to 20% for placebo, and 33% of the participants met remission criteria by day five following a single administration. [15] After one week, 78% of responders still showed an antidepressant response, and after 15 days, 42% did so. [15] In the study, half of the participants had to have their dose lowered due to a high incidence of dissociative side effects at the higher doses. [15] Development was stopped due to incidence of QTc prolongation. [15] Other NR2B subunit-selective antagonists of the NMDA receptor are still under development for depression, such as rislenemdaz (CERC-301, MK-0657). [15]

See also

Related Research Articles

NMDA receptor 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.

Dizocilpine

Dizocilpine (INN), also known as MK-801, is a uncompetitive antagonist 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.

Felbamate

Felbamate is an anticonvulsant used in the treatment of epilepsy. It is used to treat partial seizures in adults and partial and generalized seizures associated with Lennox–Gastaut syndrome in children. However, an increased risk of potentially fatal aplastic anemia and/or liver failure limit the drug's usage to severe refractory epilepsy.

NMDA receptor antagonist Class of anesthetics

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 Chemical compound

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.

GRIN2B Protein-coding gene in the species Homo sapiens

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.

GRIN2A

Glutamate [NMDA] receptor subunit epsilon-1 is a protein that in humans is encoded by the GRIN2A gene. The canonical GluN2A subunit isoform encompasses 1464 amino acids. Alternative splicing can generate a primate-specific GluN2A-short isoform.

GRIN1 Protein-coding gene in the species Homo sapiens

Glutamate [NMDA] receptor subunit zeta-1 is a protein that in humans is encoded by the GRIN1 gene.

GRIN3A Protein-coding gene in the species Homo sapiens

Glutamate [NMDA] receptor subunit 3A is a protein that in humans is encoded by the GRIN3A gene.

GRIN2D

Glutamate [NMDA] receptor subunit epsilon-4 is a protein that in humans is encoded by the GRIN2D gene.

GRIN3B

Glutamate [NMDA] receptor subunit 3B is a protein that in humans is encoded by the GRIN3B gene.

Selfotel 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.

Neramexane

Neramexane is a drug related to memantine, which acts as an NMDA antagonist and has neuroprotective effects. It is being developed for various possible applications, including treatment of tinnitus, Alzheimer's disease, drug addiction and as an analgesic. Animal studies have also suggested antidepressant and nootropic actions, so there are a wide range of potential applications this drug may be used for. It also acts as a nicotinic acetylcholine receptor antagonist.

2-Methyl-6-(phenylethynyl)pyridine

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.

Rapastinel

Rapastinel (INN) (former developmental code names GLYX-13, BV-102) is a novel antidepressant that is under development by Allergan (previously Naurex) as an adjunctive therapy for the treatment of treatment-resistant major depressive disorder. It is a centrally active, intravenously administered (non-orally active) amidated tetrapeptide (Thr-Pro-Pro-Thr-NH2) that acts as a selective, weak partial agonist (mixed antagonist/agonist) of an allosteric site of the glycine site of the NMDA receptor complex (Emax ≈ 25%). The drug is a rapid-acting and long-lasting antidepressant as well as robust cognitive enhancer by virtue of its ability to both inhibit and enhance NMDA receptor-mediated signal transduction.

7-Chlorokynurenic acid 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.

Apimostinel

Apimostinel is an antidepressant, acting as a selective partial agonist of an allosteric site of the glycine site of the NMDA receptor complex, which is under investigation by Naurex and Allergan for the treatment of major depressive disorder (MDD). As of 2015, an intravenous formulation of apimostinel is in a phase II clinical trial for MDD, and an oral formulation is concurrently in phase I trials for MDD.

Rislenemdaz Chemical compound

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.

4-Chlorokynurenine

L-4-Chlorokynurenine is an orally active small molecule prodrug of 7-chlorokynurenic acid, a NMDA receptor antagonist. It was investigated as a potential rapid-acting antidepressant.

References

  1. ↑ Chenard BL, Bordner J, Butler TW, Chambers LK, Collins MA, De Costa DL, Ducat MF, Dumont ML, Fox CB, Mena EE (August 1995). "(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: a potent new neuroprotectant which blocks N-methyl-D-aspartate responses". Journal of Medicinal Chemistry. 38 (16): 3138–45. doi:10.1021/jm00016a017. PMID   7636876.
  2. ↑ Brimecombe JC, Boeckman FA, Aizenman E (September 1997). "Functional consequences of NR2 subunit composition in single recombinant N-methyl-D-aspartate receptors". Proceedings of the National Academy of Sciences of the United States of America. 94 (20): 11019–24. Bibcode:1997PNAS...9411019B. doi: 10.1073/pnas.94.20.11019 . PMC   23569 . PMID   9380752.
  3. ↑ Di X, Bullock R, Watson J, Fatouros P, Chenard B, White F, Corwin F (November 1997). "Effect of CP101,606, a novel NR2B subunit antagonist of the N-methyl-D-aspartate receptor, on the volume of ischemic brain damage off cytotoxic brain edema after middle cerebral artery occlusion in the feline brain". Stroke: A Journal of Cerebral Circulation. 28 (11): 2244–51. doi:10.1161/01.str.28.11.2244. PMID   9368572.
  4. ↑ Taniguchi K, Shinjo K, Mizutani M, Shimada K, Ishikawa T, Menniti FS, Nagahisa A (November 1997). "Antinociceptive activity of CP-101,606, an NMDA receptor NR2B subunit antagonist". British Journal of Pharmacology . 122 (5): 809–12. doi:10.1038/sj.bjp.0701445. PMC   1565002 . PMID   9384494.
  5. ↑ Steece-Collier K, Chambers LK, Jaw-Tsai SS, Menniti FS, Greenamyre JT (May 2000). "Antiparkinsonian actions of CP-101,606, an antagonist of NR2B subunit-containing N-methyl-d-aspartate receptors". Experimental Neurology. 163 (1): 239–43. doi:10.1006/exnr.2000.7374. PMID   10785463. S2CID   23889057.
  6. ↑ Nash JE, Ravenscroft P, McGuire S, Crossman AR, Menniti FS, Brotchie JM (August 2004). "The NR2B-selective NMDA receptor antagonist CP-101,606 exacerbates L-DOPA-induced dyskinesia and provides mild potentiation of anti-parkinsonian effects of L-DOPA in the MPTP-lesioned marmoset model of Parkinson's disease". Experimental Neurology. 188 (2): 471–9. doi:10.1016/j.expneurol.2004.05.004. PMID   15246846. S2CID   41219412.
  7. ↑ Merchant RE, Bullock MR, Carmack CA, Shah AK, Wilner KD, Ko G, Williams SA (1999). "A double-blind, placebo-controlled study of the safety, tolerability and pharmacokinetics of CP-101,606 in patients with a mild or moderate traumatic brain injury". Annals of the New York Academy of Sciences. 890 (1): 42–50. Bibcode:1999NYASA.890...42M. doi:10.1111/j.1749-6632.1999.tb07979.x. PMID   10668412. S2CID   25863512.
  8. ↑ Chazot PL (November 2000). "CP-101606 Pfizer Inc". Current Opinion in Investigational Drugs. 1 (3): 370–4. PMID   11249721.
  9. ↑ Kundrotiene J, Cebers G, Wägner A, Liljequist S (January 2004). "The NMDA NR2B subunit-selective receptor antagonist, CP-101,606, enhances the functional recovery the NMDA NR2B subunit-selective receptor and reduces brain damage after cortical compression-induced brain ischemia". Journal of Neurotrauma. 21 (1): 83–93. doi:10.1089/089771504772695977. PMID   14987468.
  10. ↑ Wang CX, Shuaib A (April 2005). "NMDA/NR2B selective antagonists in the treatment of ischemic brain injury". Current Drug Targets. CNS and Neurological Disorders. 4 (2): 143–51. doi:10.2174/1568007053544183. PMID   15857299.
  11. ↑ Yurkewicz L, Weaver J, Bullock MR, Marshall LF (December 2005). "The effect of the selective NMDA receptor antagonist traxoprodil in the treatment of traumatic brain injury". Journal of Neurotrauma. 22 (12): 1428–43. doi:10.1089/neu.2005.22.1428. PMID   16379581.
  12. ↑ Löscher W, Rogawski MA (2002). "Chapter 3: Epilepsy". In Lodge D, Danysz W, Parsons CG (eds.). Ionotropic Glutamate Receptors as Therapeutic Targets. FP Graham Publishing Co., Johnson City, TN. pp. 91–132.
  13. ↑ Preskorn SH, Baker B, Kolluri S, Menniti FS, Krams M, Landen JW (December 2008). "An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder". Journal of Clinical Psychopharmacology. 28 (6): 631–7. doi:10.1097/JCP.0b013e31818a6cea. PMID   19011431. S2CID   29461252.
  14. ↑ Nicholson KL, Mansbach RS, Menniti FS, Balster RL (December 2007). "The phencyclidine-like discriminative stimulus effects and reinforcing properties of the NR2B-selective N-methyl-D-aspartate antagonist CP-101 606 in rats and rhesus monkeys". Behavioural Pharmacology. 18 (8): 731–43. doi:10.1097/FBP.0b013e3282f14ed6. PMID   17989511. S2CID   32577038.
  15. 1 2 3 4 5 6 Machado-Vieira R, Henter ID, Zarate CA (2017). "New targets for rapid antidepressant action". Prog. Neurobiol. 152: 21–37. doi:10.1016/j.pneurobio.2015.12.001. PMC   4919246 . PMID   26724279.
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