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Role of nmda receptors and drugs affecting it

  1. Role of NMDA receptors and drugs affecting it • Dr. Ashishkumar Baheti • JR 2 Pharmacology • 28/07/2020
  2. Introduction NMDA receptors Role of Glutamate receptors Drugs acting on NMDA receptors Conclusion
  3. 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
  4. 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.
  5. 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
  6. 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.
  7. 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.
  8. Drugs acting on NMDA receptors
  9. 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
  10. 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
  11. 1. NMDAR-channel blockers 1. Ketamine 2. Dizocilpine 3. Memantine 4. Phencyclidine 5. Magnesium
  12. 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
  13. 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
  14. 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.
  15. 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.
  16. 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.
  17. 2. Competitive antagonists  Glutamate site antagonists: 1. Selfotel  Glycine site antagonists 1. Felbamate 2. 7- Chlorokynurenate
  18. 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.
  19. 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.
  20. 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
  21. 3. Non-competitive antagonists 1. Amantadine 2. Riluzole 3. Eliprodil 4. Nitrous oxide 5. Acamprosate
  22. 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)
  23. 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.
  24. 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.
  25. 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).
  26. 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.
  27. 4. Newer drugs •Remacemide •Dimebon •Bryostatin •Nefiracetam •Delucemine •Glycine, d-alanine and d-cycloserine
  28. 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.
  29. 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
  30. 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
  31. 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.
  32. 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
  33. 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.
  34. Thank you!

Editor's Notes

  1. Glutamate – Glutamine cycle
  2. AMPA and kainate – non NMDA