NMDA antagonist
NMDA receptor antagonist
- Open-channel pore block (PCP or Mg²⁺ site)
- “Trapping” = how readily the drug lodges in the open pore
- Greater trapping → more dissociation
- Plugs the ion channel pore of the receptor at the phencyclidine (PCP) binding site
- The strength of an NMDA receptor antagonist is described as “trapping” behavior, i.e., how likely it is to become lodged in the pore, leading to prolonged inhibition of calcium influx into the neuron
- ➔ protects against excitotoxicity in conditions of excessive glutamate release, but may contribute to NMDA receptor hypofunction → elevated KYNA is associated with schizophrenia
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 — Dextromethorphan's active metabolite; the NMDA antagonism behind both the dissociative effect and the 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 — The S-enantiomer of methadone: little mu activity, weak NMDA antagonism, most of the hERG/QT liability.
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