Traxoprodil Explained

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. After one week, 78% of responders still showed an antidepressant response, and after 15 days, 42% did so. 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. Development was stopped due to incidence of QTc prolongation. Other NR2B subunit-selective antagonists of the NMDA receptor are still under development for depression, such as rislenemdaz (CERC-301, MK-0657).

See also

• List of investigational antidepressants

Notes and References

1. Chenard BL, Bordner J, Butler TW, Chambers LK, Collins MA, De Costa DL, Ducat MF, Dumont ML, Fox CB, Mena EE . (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 . August 1995 . 7636876 . 10.1021/jm00016a017.
2. Brimecombe JC, Boeckman FA, Aizenman E . 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 . September 1997 . 9380752 . 23569 . 10.1073/pnas.94.20.11019. 1997PNAS...9411019B . free .
3. Di X, Bullock R, Watson J, Fatouros P, Chenard B, White F, Corwin F . 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 . November 1997 . 9368572 . 10.1161/01.str.28.11.2244.
4. Taniguchi K, Shinjo K, Mizutani M, Shimada K, Ishikawa T, Menniti FS, Nagahisa A . Antinociceptive activity of CP-101,606, an NMDA receptor NR2B subunit antagonist . . 122 . 5 . 809–12 . November 1997 . 9384494 . 1565002 . 10.1038/sj.bjp.0701445 .
5. Steece-Collier K, Chambers LK, Jaw-Tsai SS, Menniti FS, Greenamyre JT . Antiparkinsonian actions of CP-101,606, an antagonist of NR2B subunit-containing N-methyl-d-aspartate receptors . Experimental Neurology . 163 . 1 . 239–43 . May 2000 . 10785463 . 10.1006/exnr.2000.7374 . 23889057 .
6. Nash JE, Ravenscroft P, McGuire S, Crossman AR, Menniti FS, Brotchie JM . 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 . August 2004 . 15246846 . 10.1016/j.expneurol.2004.05.004 . 41219412 .
7. Merchant RE, Bullock MR, Carmack CA, Shah AK, Wilner KD, Ko G, Williams SA . 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 . 42–50 . 1999 . 1 . 10668412 . 10.1111/j.1749-6632.1999.tb07979.x. 1999NYASA.890...42M . 25863512 .
8. Chazot PL . CP-101606 Pfizer Inc . Current Opinion in Investigational Drugs . 1 . 3 . 370–4 . November 2000 . 11249721 .
9. Kundrotiene J, Cebers G, Wägner A, Liljequist S . 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 . January 2004 . 14987468 . 10.1089/089771504772695977 .
10. Wang CX, Shuaib A . NMDA/NR2B selective antagonists in the treatment of ischemic brain injury . Current Drug Targets. CNS and Neurological Disorders . 4 . 2 . 143–51 . April 2005 . 15857299 . 10.2174/1568007053544183.
11. Yurkewicz L, Weaver J, Bullock MR, Marshall LF . The effect of the selective NMDA receptor antagonist traxoprodil in the treatment of traumatic brain injury . Journal of Neurotrauma . 22 . 12 . 1428–43 . December 2005 . 16379581 . 10.1089/neu.2005.22.1428 .
12. Book: Löscher W, Rogawski MA . Lodge D, Danysz W, Parsons CG . Ionotropic Glutamate Receptors as Therapeutic Targets . FP Graham Publishing Co., Johnson City, TN . 2002 . 91–132 . Chapter 3: Epilepsy.
13. Preskorn SH, Baker B, Kolluri S, Menniti FS, Krams M, Landen JW . 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 . December 2008 . 19011431 . 10.1097/JCP.0b013e31818a6cea . 29461252 .
14. Nicholson KL, Mansbach RS, Menniti FS, Balster RL . 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 . December 2007 . 17989511 . 10.1097/FBP.0b013e3282f14ed6 . 32577038 .
15. Machado-Vieira R, Henter ID, Zarate CA . New targets for rapid antidepressant action . Prog. Neurobiol. . 152 . 21–37 . 2017 . 26724279 . 10.1016/j.pneurobio.2015.12.001 . 4919246.