NMDA antagonist
NMDA receptor antagonist
- Open-channel pore block (PCP or Mg²⁺ site)
- “Trapping” = how readily the drug lodges in the open pore
- NMDA antagonist “trapping”: likelihood of lodging in the pore and prolonging inhibition of neuronal calcium influx
- protects against excitotoxicity in conditions of excessive glutamate release, but may contribute to NMDA receptor hypofunction → elevated KYNA is associated with schizophrenia
- Greater trapping → more dissociation
Drugs with this mechanism (22)
- Agmatine — Endogenous polyamine; NMDA and imidazoline modulator sold as a supplement.
- Amantadine — NMDA antagonist with uncertain dopaminergic actions; used for Parkinson symptoms and levodopa dyskinesia.
- Dextromethorphan — OTC cough suppressant; NMDA antagonist and sigma-1 agonist, dissociative in overdose.
- Dextrorphan — Active dextromethorphan metabolite; NMDA antagonism drives dissociation and abuse potential.
- Dizocilpine — MK-801; the prototypical potent NMDA channel blocker (research).
- Esketamine — Intranasal NMDA antagonist for treatment-resistant depression; REMS, in-clinic dosing.
- Amantadine ER — Extended-release amantadine for levodopa dyskinesia and off episodes in Parkinson disease.
- Guaifenesin — OTC expectorant; NMDA antagonism is incidental to its unclear clinical action.
- Ibogaine — Psychoactive alkaloid studied for addiction; cardiac (QT) risk.
- Ketamine — Dissociative NMDA antagonist anesthetic; rapid antidepressant at subanesthetic doses.
- Levorphanol — Potent long-acting mu-opioid agonist for severe pain; accumulation complicates titration.
- Magnesium — Essential cation and physiologic NMDA-channel blocker; anticonvulsant in eclampsia.
- Magnesium sulfate — IV magnesium; first-line for eclampsia and torsades de pointes.
- Memantine — NMDA antagonist for moderate-to-severe Alzheimer dementia; well tolerated.
- Methadone — Full mu agonist for OUD and pain; long, variable half-life, QT prolongation.
- Memantine XR — Extended-release NMDA antagonist for moderate-to-severe Alzheimer disease.
- Nitrous oxide — Rapid inhaled NMDA-antagonist analgesic and anesthetic; repeated exposure depletes vitamin B12.
- Noribogaine — Long-acting active metabolite of ibogaine.
- Orphenadrine — Anticholinergic muscle relaxant with NMDA activity.
- Phencyclidine — Phencyclidine; a dissociative NMDA antagonist causing agitation and psychosis.
- R-Methadone — The active R-enantiomer of methadone (opioid effect).
- S-Methadone — Methadone S-enantiomer: little mu activity, weak NMDA antagonism, most of the hERG/QT liability.
Self-check
- What does greater NMDA antagonist trapping predict?
More dissociation. - What does trapping describe at the NMDA receptor?
How readily the drug lodges in the open pore.
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