NMDA receptors and drugs acting on them

NMDA

1. NMDA RECEPTORS AND DRUGS ACTING ON THEM

2. CONTENTS Excitatory neurotransmitter  Glutamate Types of glutamate receptors NMDA receptor Drugs acting on it.

3. GLUTAMATE Principal excitatory neurotransmitter Widely and uniformly distributed in CNS Derived from: Glucose via Kreb’s cycle * Glutamine by glial cells.

4. GLUTAMATE Stored in synaptic vesicles Released by Ca 2+ dependent exocytosis Taken up by Na + /H + /K + dependent transporters Action terminated by carrier mediated reuptake into nerve terminals and neighboring astrocytes.

5. GLUTAMATE RECEPTOR SUBTYPES Metabotropic (G-protein coupled receptors) Ionotropic (Ligand gated ion channels)

6. METABOTROPIC RECEPTORS 8 different receptor types (mGlu 1-8) Functions as homodimers cross-linked by a disulfide bridge across extracellular domain of each protein. Divided into 3 groups.

7. IONOTROPIC RECEPTORS 3 main subtypes: NMDA  N-methyl D-aspartic acid AMPA α - amino-3-hydroxy-5-methylisoxazole-4-propionic acid Kainate International Union of Basic and Clinical Pharmacology (IUPHAR)

8. IONOTROPIC RECEPTORS NMDA receptors  7 subunits GluN1; GluN2A; GluN2B; GluN2C; GluN2D; GluN3A; GluN3B AMPA receptors GluA1-4 Kainate receptors GluK1-5

9. NMDA RECEPTOR Most important receptor Involved in processes like- M emory acquisition D evelopment of synaptic plasticity Epilepsy N euronal excitotoxicity due to cerebral ischemia.

10. NMDA RECEPTOR Pentamer; High permeability to Ca 2+ Widely distributed in spinal cord, hippocampus, cerebral cortex, glial cells.

11. NMDA RECEPTOR 6 pharmacologically distinct binding sites/modulatory sites: Glu (or NMDA) binding site Modulatory site for glycine Polyamines regulatory sites Phencyclidine binding site Voltage dependent Mg 2+ binding site Voltage independent Zn 2+ binding site.

12. INTERACTIONS BETWEEN GLUTAMATE RECEPTORS Important role in: Long term adaptive changes  synaptic plasticity Pathologic changes in brain excitotoxicity

13. SYNAPTIC PLASTICITY Long term changes in synaptic connectivity & efficacy following: Physiological alterations in neuronal activity (memory & learning) Pathological disturbances (Epilepsy, pain, drug dependence) Mechanism  Long Term Potentiation AMPA & NMDA play central role.

14. LONG TERM POTENTIATION Prolonged enhancement of synaptic transmission  short burst of high frequency presynaptic stimulation Long term depression produced at some synapses by longer train of stimuli and lower frequency. Characteristic feature enhancement of synaptic strength following simultaneous activity in both pre & postsynaptic neurons.

15. LONG TERM POTENTIATION LTP initiation  results from enhanced activation of postsynaptic AMPA receptors at EAA synapse enhances glutamate release. Response of postsynaptic AMPA increased due to phosphorylation of AMPA subunits conductance enhanced. NMDA in LTP: Voltage dependent channel block by Mg 2+ High Ca 2+ permeability.

16. LONG TERM POTENTIATION Normal membrane potential  NMDA channel blocked Mg 2+ . Sustained post synaptic depolarization glutamate acting on AMPA removes Mg 2+ block NMDA receptor activation Ca 2+ entry Induction phase phosphorylation of AMPA increased responsiveness to glutamate Maintenance phase more AMPA recruited to membrane of post synaptic dendritic spines result of altered receptor trafficking.

17. EXCITOTOXICITY Glutamate  highly toxic to neurons excitotoxicity “Chinese restaurant syndrome”. Local injection of Glutamate agonist Kainic acid excitation of local glutamate releasing neurons release of glutamate acting on NMDA and metabotropic receptors neuronal death. Calcium overload.

18. MECHANISMS Activation of NMDA  depolarization NMDA channel unblock permits Ca 2+ entry. Also opens voltage activated Ca 2+ channels releasing more glutamate. Activation of metabotropic receptors release of intracellular Ca 2+ from ER; Na + ; Ca 2+ entry stimulates Na + /Ca 2+ exchange; Depolarisation inhibits/reverses glutamate uptake increasing extracellular glutamate concentration

19. DRUGS ACTING ON NMDA RECEPTORS Kynurenic acid Ketamine Phencyclidine Dizocelpine Remacemide Memantine Ethyl alcohol Amantidine Selfotel Eliprodel Dextromethorphan Nitrous oxide Xenon Felbamate Acamprost

20. KETAMINE AND PHENCYCLIDINE Together classified as “Club Drugs” Sold under the names “Angel dust”, “Hog”, “Special K”. Non competitive antagonists of NMDA receptors Pure forms  white crystalline powders. Also available as liquids, capsules/ pills. Psychedelic effects 1 hour.

21. KETAMINE Congener of phencyclidine. Partially water soluble; Highly lipid soluble. Dissociative anesthesia. MOA  Inhibition of NMDA receptor complex.

22. KETAMINE ACTIONS: Analgesia Stimulation of sympathetic nervous system Bronchodilation Minimal respiratory depression Route of Administration  IV, IM Dose: 1-2 mg/kg IV or 4-6mg/kg IM ADR: Psychomimetic effects.

23. ACAMPROSATE Antagonist of NMDA glutamate receptor Interferes with forms of synaptic plasticity that depend on NMDA receptors. Use: R x alcoholism ADR: Allergic reactions; Arrhythmia; BP variations; Headache; Insomnia; Impotence; Hallucinations in elderly patients.

24. MEMANTINE Excitotoxic activation of glutamate transmission via NMDA receptors  Contributes to pathophysiology of Alzheimer’s disease. Memantine  binds to NMDA receptor channels- produces a non competitive blockade. Less toxic and better tolerated than other cholinesterase inhibitors.

25. AMANTADINE Antiviral agent Weak antiparkinsonism properties. An antagonist of NMDA receptor Uses: Parkinson’s Disease Iatrogenic dyskinesia.

26. FELBAMATE Effective for partial seizures. Causes aplastic anemia and severe hepatitis. MOA: Produces use-dependent block of NMDA receptor with selectivity for NR1-2B subtype. Produces barbiturate like potentiation of GABA A receptor responses.

27. FLUPIRTINE Neither an opioid analgesic or a NSAID Not yet approved by US FDA Permission granted to carry out phase II trial for R x of fibromyalgia.

28. FLUPIRTINE- MECHANISM OF ACTION Acts indirectly as NMDA receptor antagonist by activation of K + channels  hyperpolarization of neuronal membrane neuron becomes less excitable. C auses a dose-dependent reduction of NMDA receptor mediated glutamate induced rise in intracellular Ca ++   concentration Analgesic, Muscle relaxant, Antiparkinsonian

29. Idrocilamide ; Riluzole  newer drugs for treatment of Amyotrophic Lateral Sclerosis (ALS). Spasm reducing effects possibly through inhibition of glutamatergic transmission in CNS.

30. REFERENCES Essential Psychopharmacology- Stephen M Stahl Rang and Dales pharmacology . Basic and clinical pharmacology – Katzung . Prinicples of Pharmacology- Sharma Harish S, Bhuvana K, Bengalorkar GM, Kumar T. Flupirtine : Clinical pharmacology.  Journal of Anaesthesiology , Clinical Pharmacology . 2012;28(2):172-177. doi:10.4103/0970-9185.94833.

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