NMDA RECEPTORS AND DRUGS ACTING ON

THEM

CONTENTS

• Excitatory neurotransmitter Glutamate

• Types of glutamate receptors

•NMDA receptor

•Drugs acting on it.

GLUTAMATE

• Principal excitatory neurotransmitter

•Widely and uniformly distributed in CNS

•Derived from:

• Glucose via Kreb’s cycle *

• Glutamine by glial cells.

GLUTAMATE

• Stored in synaptic vesicles

• Released by Ca2+ dependent exocytosis

• Taken up by Na+/H+/K+ dependent transporters

•Action terminated by carrier mediated reuptake into nerve terminals and neighboring astrocytes.

GLUTAMATE RECEPTOR SUBTYPES

•Metabotropic (G-protein coupled receptors)

• Ionotropic (Ligand gated ion channels)

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.

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)

IONOTROPIC RECEPTORS

•NMDA receptors 7 subunits GluN1; GluN2A; GluN2B;

GluN2C; GluN2D; GluN3A; GluN3B

•AMPA receptors GluA1-4

•Kainate receptors GluK1-5

NMDA RECEPTOR

•Most important receptor

• Involved in processes like-

• Memory acquisition

• Development of synaptic plasticity

• Epilepsy

• Neuronal excitotoxicity due to cerebral ischemia.

NMDA RECEPTOR

• Pentamer; High permeability to Ca2+

•Widely distributed in spinal cord, hippocampus, cerebral cortex, glial cells.

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 Mg2+ binding site

Voltage independent Zn2+ binding site.

INTERACTIONS BETWEEN GLUTAMATE RECEPTORS• Important role in:

• Long term adaptive changes synaptic plasticity

• Pathologic changes in brain excitotoxicity

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.

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.

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 Mg2+

• High Ca2+ permeability.

LONG TERM POTENTIATION• Normal membrane potential NMDA channel blocked Mg2+.

• Sustained post synaptic depolarization glutamate acting on AMPA removes Mg2+ block NMDA receptor activation Ca2+ 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.

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.

MECHANISMS• Activation of NMDA depolarization NMDA channel unblock

permits Ca2+ entry.

• Also opens voltage activated Ca2+ channels releasing more glutamate.

• Activation of metabotropic receptors release of intracellular Ca2+ from ER; Na+; Ca2+ entry stimulates Na+/Ca2+ exchange;

• Depolarisation inhibits/reverses glutamate uptake increasing extracellular glutamate concentration

DRUGS ACTING ON NMDA RECEPTORS• Kynurenic acid

• Ketamine

• Phencyclidine

• Dizocelpine

• Remacemide

• Memantine

• Ethyl alcohol

• Amantidine

• Selfotel

• Eliprodel

• Dextromethorphan

• Nitrous oxide

• Xenon

• Felbamate

• Acamprost

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.

KETAMINE

• Congener of phencyclidine.

• Partially water soluble; Highly lipid soluble.

• Dissociative anesthesia.

• MOA Inhibition of NMDA receptor complex.

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.

ACAMPROSATE

• Antagonist of NMDA glutamate receptor

• Interferes with forms of synaptic plasticity that depend on NMDA receptors.

• Use: Rx alcoholism

• ADR: Allergic reactions; Arrhythmia; BP variations; Headache; Insomnia; Impotence; Hallucinations in elderly patients.

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.

AMANTADINE

•Antiviral agent

•Weak antiparkinsonism properties.

•An antagonist of NMDA receptor

•Uses:• Parkinson’s Disease• Iatrogenic dyskinesia.

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 GABAA receptor

responses.

FLUPIRTINE

•Neither an opioid analgesic or a NSAID

•Not yet approved by US FDA

• Permission granted to carry out phase II trial for Rx of

fibromyalgia.

FLUPIRTINE- MECHANISM OF ACTION

•Acts indirectly as NMDA receptor antagonist by activation of K+ channels hyperpolarization of neuronal membrane neuron becomes less excitable.

• Causes a dose-dependent reduction of NMDA receptor mediated glutamate induced rise in intracellular Ca+

+ concentration

•Analgesic, Muscle relaxant, Antiparkinsonian

• Idrocilamide; Riluzole newer drugs for treatment of Amyotrophic Lateral Sclerosis (ALS).

• Spasm reducing effects possibly through inhibition of glutamatergic transmission in CNS.

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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