Role of NMDA receptors and drugs affecting it
• Dr. Ashishkumar Baheti
• JR 2 Pharmacology
• 28/07/2020

Introduction
NMDA receptors
Role of Glutamate receptors
Drugs acting on NMDA receptors
Conclusion

Introduction
• Glutamate is the main stimulatory amino acid in brain.
• Location – widely and uniformly distributed in CNS
• Stored in synaptic vesicles
• Released by ca dependent exocytosis

Fig1. Transport of glutamate (Glu) and glutamine (Gln) by neurons and astrocytes.
Released glutamate is captured partly by neurons and partly by astrocytes, which convert most of it to
glutamine. EAAT, excitatory amino acid transporter;
GlnT, glutamine transporter;
VGluT, vesicular glutamate transporter.

The NMDA receptor is an ionotropic receptor.
The receptor is a heteromeric complex and it interacts with multiple
intracellular proteins by 7 subunits: GluN1, GluN2A-2D and GluN3A-3B.
Widely distributed in spinal cord, hippocampus, cerebral cortex and glial
cells.
Involved in processes like :
Memory
Learning
Thinking
Reward and pleasure

Special features of NMDA receptors
• They are highly permeable to Ca2+, as well as to other cations, so
activation of NMDA receptors is particularly effective in promoting Ca2+
entry.
• They are readily blocked by Mg2+, and this block shows marked
voltage dependence. It occurs at physiological Mg2+ concentrations
when the cell is normally polarised, but disappears if the cell is
depolarised.
• Activation of NMDA receptors requires glycine as well as glutamate.
The binding site for glycine is distinct from the glutamate binding site,
and both have to be occupied for the channel to open.

ROLE OF GLUTAMATE RECEPTORS
• Synaptic plasticity - It is a general term to describe long-term
changes in synaptic connectivity and efficacy due to increased
synaptic proliferation and connectivity. It occurs due to
continued learning efforts resulting in improved memory
• Excitotoxicity – Glutamate is highly toxic to neurons.
Excitotoxicity results from a sustained rise in intracellular Ca2+
concentration (Ca2+ overload). Excitotoxicity is a contributing
factor in various neurodegenerative diseases
• Long term potentiation - Long term enhancement of synaptic
transmission following a short burst of presynaptic stimulation
(conditioning) at high frequency.

Drugs acting on NMDA receptors

DRUGS
Three major classes of antagonists –
1. NMDAR-channel blockers
they bind to sites within the NMDAR channel pore
2. Competitive antagonists
a. Glutamate site antagonists
b. Glycine site antagonists
3. Non-competitive NMDAR antagonists
allosteric inhibitors
4. Newer drugs

Mechanism Drug
1. NMDA channel blockers
1. Ketamine, Methoxetamine
2. Dizocilpine
3. Memantine, Nitromemantine, Neramexane
4.Phencyclidine and derivatives
5.Magnesium
2. Competitive antagonists
a. Glutamate site antagonists 1. Selfotel
b. Glycine site Antagonists 1. Felbamate
2. 7-chlorokyurenic acid
3. Non competitive antagonists 1. Amantadine
2. Nitrous oxide
3. Eliprodil
4. Riluzole
5. Acamprosate
4. Newer drugs

1. NMDAR-channel blockers
1. Ketamine
2. Dizocilpine
3. Memantine
4. Phencyclidine
5. Magnesium

1. KETAMINE
MOA :- NMDAR channel blocker, acts at Thalamo cortical junction.
Produces dissociative anaesthesia
ADR :- It is a phencyclidine derivative. Hallucination, ↑BP, ↑HR, ↑ICP, ↑IOP
Uses :- induction of anaesthesia, short surgical procedures, burn dressings

2. Dizocilpine
MOA: NMDA receptor channel blocker, Nicotinic acetylcholine receptor
antagonist, Inhibits serotonin and dopamine transport as well
Its an experimental compound
Uses: It is tried in animal models for Stroke, Traumatic brain injury,
Neurodegenerative diseases e.g. Huntington’s disease, Alzheimer’s, ALS

3. Memantine
MOA: Memantine, an NMDA receptor channel blocker, protects neurons from
calcium-mediated neurodegeneration which forms the basis of
pathophysiology of primary dementias .
Uses: it is approved by the U.S. F.D.A and the European Medicines Agency for
treatment of moderate-to-severe Alzheimer's disease.
It is better tolerated and less toxic than cholinesterase inhibitors.

Neramexane
Memantine analogue with nootropic, antidepressant properties.
Also a Nicotinic acetylcholine antagonist.
It is under Phase III clinical trials for use in Alzheimer’s disease, tinnitus, drug
dependence, depression and pain.

4. Phencyclidine (PCP or angel dust)
Originally developed as anesthetic. Drug of abuse in 1970; both oral & smoking.
Dissociative anesthesia
Mild hallucinatory effects like - disorientation, distorted body images, loss of sense of time, emotional
withdrawal and impaired thought processes.
At higher doses may cause muscle rigidity, rhabdomyolysis, hyperthermia, coma and death. Treatment
includes Life support, no specific antidote.
Tenocyclidine, Gacyclidine, Eticyclidine, Rolicyclidine, Methoxydine are newer drugs with similar action
to phencyclidine.
Better affinity for NMDA receptor, less hallucinogenic, less or no addiction or abuse liability.

2. Competitive antagonists
 Glutamate site antagonists:
1. Selfotel
 Glycine site antagonists
1. Felbamate
2. 7- Chlorokynurenate

Glutamate site antagonist: Selfotel
MOA: Competitive NMDA antagonist,
directly competing with Glutamate for binding to the receptor.
Uses: Initial studies showed anticonvulsant, anxiolytic, analgesic
and neuroprotective effects, and it was originally researched for the treatment
of stroke.
But subsequent animal and human studies showed PCP-like effects, as well as limited
efficacy and evidence for possible neurotoxicity under some conditions and so
clinical development was ultimately discontinued.

Glycine site antagonists - 1. Felbamate
MOA – competitively blocks NMDAR at the glycine site.
Blocks voltage gated Na channels
Use - Partial seizures, GTCS, Lennox-Gastaut Syndrome.
ADR - Increase incidence of unpredictable aplastic anemias/ bone marrow
suppression and hepatotoxicity. Hence withdrawn from the market in many
countries.

2. 7-Chlorokynurenate
Glycine site antagonist
It is under investigation for chronic hyperalgesic states.
Prostaglandin E2 (PGE2) induced hyperalgesia can be blocked
Phase II trial

3. Non-competitive antagonists
1. Amantadine
2. Riluzole
3. Eliprodil
4. Nitrous oxide
5. Acamprosate

1. Amantadine
• MOA: not clear
• release of DA and blockade of reuptake of DA;
• blocks the NMDA glutamate receptor.
Use :
• In early Parkinsons disease
• In combination with levodopa in certain cases
• dyskinesia
Dose – 100 mg BD
ADR
• Insomnia, dizziness, confusion, hallucinations.
• Ankle oedema
• Livedo reticularis (skin pigmentation)

2. Riluzole
MOA: inhibition of Presynaptic Voltage dependant sodium channel, Inhibition of
glutamate release, Blockage of NMDA and kianate receptors
Uses: Approved for Amyotrophic Lateral Sclerosis (ALS)
Others– antiepileptic, neurodegenerative dis., psychiatric dis.- BPD, anxiety, OCD
Dose – 50 mg BD
ADR: Nausea, diarrhoea, weight loss, Increased liver enzymes.

3. Eliprodil (SL-820715)
•MOA: NMDA antagonist binding to the polyamine
modulatory site.
•Uses: Neuroprotective & anticonvulsant effect in
animal studies; does not produce sedation &
amnesia,
•Phase III trials for the treatment of acute ischemic
stroke with eliprodil showed no efficacy on futility
analysis, and accordingly, the trial was stopped.

4. Nitrous oxide
•Inhalational anesthetic. Neither inflammable nor
explosive.
•MOA: Facilitate GABA mediated inhibition and Inactivation
of NMDA mediated excitation.
•Uses: Maintainance of surgical anesthesia. Strong
analgesic action, rapid induction & recovery.
• ADRs: Exposure of more than 4 hrs can cause
megaloblastic changes in bone marrow, increase volume of
body compartments causing Pneumothorax, increased
pressure inside sinuses (nasal, eye, middle ear).

5. Acamprosate
MOA: agonist at GABAa receptor, weak antagonist at NMDA receptor, Some opioid antagonistic
activity and increases 5-HT levels
Uses: FDA approved for alcohol deaddiction, Decreases drinking frequency, Reduces relapse
drinking in abstinent alcoholic, Efficacy similar to Naltrexone.
Dose:- 1.3 to 2 g/day
ADR: diarrhea, rash, headache.

4. Newer drugs
•Remacemide
•Dimebon
•Bryostatin
•Nefiracetam
•Delucemine
•Glycine, d-alanine and d-cycloserine

Remacemide
• binds weakly and noncompetitively to the ionic channel site of
the NMDA receptor. It binds both allosterically and in the
channel.
• However, because remacemide binds so weakly to NMDAR,
much of its in vivo effect against excitotoxicity is thought to be
caused by its metabolic transformation to the more potent
desglycine derivative FPL 12495.
• Thus, it may actually act as a prodrug to deliver the active
metabolite FPL 12495 to CNS.
• Studied in animals for: Huntington’s disease, Stroke,
Parkinson’s disease & Epilepsy.

Dimebon
Brain Cell Apoptosis Inhibitor
MOA-
• Blocks the action of neurotoxic βamyloid proteins
• Inhibits L-type calcium channels
• Modulates the action of AMPA & NMDA glutamate receptors
• Neuroprotective effect by blocking a novel target that involves mitochondrial pores
Assessed in clinical trials (phase 3) in patients with Alzheimer’s and
Huntington’s diseases

Bryostatin & Nefiracetam
•Signalling-protein modulators
•Bryostatin & Nefiracetam can activate protein
kinase C and tested in patients with Alzheimer’s
disease (phase 3)
•Nootropic and neuroprotective
•accelerates acetylcholine turnover and release
enhancing cellular communication via synapses

Delucemine
•is a drug which acts as an NMDA
antagonist and a serotonin reuptake
inhibitor, and has neuroprotective effects.
•It was originally investigated for the
treatment of stroke but is now being
studied as a potential antidepressant.
•It is currently in phase II clinical trials.

Glycine, D-serine and D-cycloserine
•The NMDA receptor stimulating agents glycine,
D-serine and D-cycloserine were evaluated as
add-ons to neuroleptic therapy.
•Glycine & D-serine improved the negative
symptoms.
•The partial agonist D-cycloserine reduced the
negative symptoms when given together with
risperidone

Conclusion:
 Glutamate is the main stimulatory amino acid in brain having both ionotropic
and metabotropic receptors.
 Glutamate receptors are involved in various processes like synaptic plasticity,
long term potentiation, excitotoxicity, memory, thinking etc.
 The NMDA receptor is an ionotropic receptor Activation of NMDA receptors
requires both glycine as well as glutamate.
 Various sites in the glutamate receptors can serve as future targets for use in
neurodegenerative diseases, psychiatric disorders, epilepsy and as anesthetics.

Thank you!