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Traxoprodil (CP-101,606) started life at Pfizer in the 1990s as a stroke and traumatic-brain-injury neuroprotectant, built around a then-novel idea: block only the GluN2B (NR2B) subunit of the NMDA receptor instead of hammering the whole channel like PCP or MK-801. The stroke program stalled over QT-interval prolongation and hallucinations at neuroprotective doses, but the NR2B-selective mechanism looked too interesting to shelve. Pfizer repurposed it, and in a 2008 proof-of-concept study led by Sheldon Preskorn it relieved treatment-resistant major depression as an add-on therapy, one of the first solid human signals that NMDA blockade could work as an antidepressant outside of ketamine itself. But the same cardiac safety baggage that killed the stroke program followed it into psychiatry, and traxoprodil never advanced to Phase III for depression.
- significant antidepressant separation from placebo in its 2008 trial
- fewer dissociative effects than nonselective NMDA blockers at effective doses
- validated NR2B as a legitimate antidepressant target
- dissociation/hallucinations at higher (neuroprotective) doses
- sedation
- Traxoprodil's depression trial design (a crossover proof-of-concept in treatment-resistant patients) became a template later reused for ketamine and other rapid-acting antidepressant studies.
- Its cardiac QT signal, first flagged in stroke trials, is the same class of side effect that later dogged several other NR2B-selective candidates.
Mechanism
Selective, non-competitive at GluN2B (NR2B) subunit-containing receptors, sparing the more broadly distributed GluN2A-containing receptors; intended to isolate mood-relevant NMDA signaling from receptors tied to cognition and motor function.
Dosingtypical ranges, not medical advice
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Safetyrisks and cautions, not medical advice
The QT prolongation is what closed this program, and it did so twice: once in stroke and brain injury, then again in depression, where the cardiac liability followed the molecule into its second indication. Dissociation is the other documented effect. A controlled Parkinson's trial recorded dose-related dissociation and amnesia at antidyskinetic doses, and the treatment-resistant depression study needed slower infusions and reduced doses to manage dissociative reactions. Against that, a 404-patient brain-injury trial using a 72-hour infusion reported it as well tolerated, so the risk tracks dose and infusion rate rather than being uniform.
History
Developed by Pfizer, first tested for acute stroke/TBI neuroprotection in the 1990s and shelved for cardiac safety; repurposed and tested as an adjunctive antidepressant in a Preskorn-led proof-of-concept trial (2008), then discontinued before Phase III.
Subjective profileweighing the evidence above
One of the earliest clean demonstrations that NR2B-selective NMDA blockade alone can lift mood, undone by a QT liability inherited from its first life as a stroke drug.
Resources
This entry is here for reference.
Research
- 1.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
- 2.CP-101,606, an NR2B subunit selective NMDA receptor antagonist, inhibits NMDA and injury induced c-fos expression and cortical spreading depression in rodents
2 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Did traxoprodil ever reach the market?
No, for either of its two intended uses. It failed as a stroke neuroprotectant on safety grounds and was never advanced past early-stage depression trials.
Why is it historically important?
Its 2008 depression trial was one of the first human proofs that selectively blocking the NR2B subunit of the NMDA receptor, not the whole channel, could produce an antidepressant effect.
Adverse effects
- dissociation/hallucinations at higher (neuroprotective) doses
- sedation
Notes and cautions
- QT interval prolongation