1. GLUTAMATE RECEPTORS

2. Overview
• History
• Introduction
• Receptor types
• Role of the receptors
• Drugs acting at receptors – agonist and
antagonists
• Recent advances

3. History
• 1950s : Various neurotransmitters
• 1970 : Glycine established as an inhibitory
transmitter
• A major advance in the amino acid
neurotransmitters was the discovery of EAA
(excitatory amino acid) antagonists by Watkins
in Bristol

4. Introduction
• In the CNS amino acids acting as
neurotransmitters (NT) are
Excitatory transmitter – Glutamate, Aspartate
Inhibitory transmitters – GABA, Glycine

6. Synthesis, storage and release of
glutamate

7. Glutamate Receptor Subtypes
• Act through
• Inotropic receptors (ligand gated ion channel)
• Metabotropic receptors

8. Ionotropic receptors
• NMDA (N-Methyl-D-aspartate) receptors :
7 subunits (GluN1, GluN2A, GluN2B, GluN2C,
GluN2D, GluN3A, GluN3B).
• AMPA (α-amino-3-hydroxy-5-methyl-4-
isoxazole propionic acid) receptors :
4 subunits (GluA1-4)
• Kainate receptors : 5 subunits (GluK1-5)

9. Metabotropic receptors
• Also called G protein coupled receptors
• Post synaptic - Group1 : mGlu 1 & 5, Gq type
• Presynaptic - Gi/Go type
• Group 2 - mGlu2 & 3
• Group 3 - mGlu4, 6, 7 & 8

13. Role of glutamate receptor
• Synaptic plasticity-
• To describe long term changes in synaptic
connectivity and efficacy either following
physiological alterations in neuronal activity
(learning and memory)
• Or pathological disturbances (as in epilepsy,
chronic pain)
• Excitotoxicity

15. Mechanism of LTP, LTD

16. Agonist and positive modulators
• AMPA receptor modulators (ampakines) may
improve memory and cognitive performance.
• Eg: Cyclothiazide, Piracetam and CX-516
(Ampalex).
• Treatment of schizophrenia, depression,
attention deficit hyperactivity disorder (ADHD)
and Parkinson's disease

17. Cyclothiazide
• Benzothiazide group of drugs
• MOA- positive allosteric modulator of AMPA
and kainate receptors.
• Reducing rapid desensitization of AMPA
• Non competitive antagonist mGluR1.
• In animals- potent convulsant.

18. Piracetam
• Cyclic derivative of GABA
• Positive allosteric modulator of AMPA receptor
• Effect on NMDA receptor – learning and
memory
• Uses: dementia, depression and anxiety

19. Agonist of metabotropic glutamate
receptor
• Group 2 and 3 mGlu receptor agonists and
positive allosteric modulators
• LY354740, DCPG
• Decrease glutamate release
• To date clinical trials have been disappointing

20. Antagonists and negative modulators

21. Drugs acting on NMDA receptors
• Glycine site blocking drugs – Kynureneic acid
• Channel blocking drugs – Ketamine,
phencyclidine, dizocilpine, remacemide,
memantine
• NMDA receptor antagonists - Riluzole, Eliprodil,
Dextromethorphan, Methadone, Amantadine

22. DRUG MOA USES/ADR
Kynureneic
acid
Antagonist at glycine binding site Antiexcitotoxic,
anticonvulsant
Ketamine Non competitive antagonist at NMDA
IM: 2–4 mg/kg, IV: 0.2–0.75 mg/kg
Anesthetic, pain
management.
ADR: High BP, cerebro-
vascular accident
Phencyclidine NMDA receptor antagonist Recreational drug
Dizocilpine NMDA receptor antagonist Anticonvulsant,
dissociative anesthetic,
stroke, Huntington's
disease etc.
Remacemide Low affinity NMDA receptor
antagonist
Stroke, epilepsy
ADR: dizziness, nausea
Memantine Non competitive NMDA receptor
antagonist -interacts with the Mg2+
binding site of the channel to prevent
excessive activation while sparing
normal function
Alzheimer's disease,
glaucoma
10–30 mg/day
ADR: confusion,
hypertonia, cystitis

23. DRUG MOA USES/DOSE/ADR
Riluzole Presynaptically inhibits glutamate
release
Post synaptically blocks postsynaptic
NMDA- and kainate-type glutamate
receptors and
inhibits voltage-dependent Na+
channels.
Amyotrophic lateral sclerosis
PO: 50mg BD
ADR: dizziness, weight loss
Amantadine Blocks NMDA glutamate receptors Parkinson's disease
(neurotoxicity, dyskinesia)
PO: 100–200mg/day
ADR: hallucination, ankle
edema.
Eliprodil NMDA antagonist (polyamine site) Failed in clinical trial III
Dextrometharphan NMDA-receptor antagonist and acts
centrally to elevate the threshold for
coughing.
Antitussive agent
PO: 10 mg TDS
Methadone NMDA receptor antagonist 2.5-10mg q8-12th hourly
ADR: sedation, fatigue
Acamprosate Weak antagonist of NMDA receptors,
activator of GABAA receptors
Anticraving drug
ADR: GIT upset, skin eruption

24. Potential therapeutic interest
• As general anesthetic agents
• Neurodegenerative disorder : Alzheimer's, Parkinson's
disease, ALS, Glaucoma
• Epilepsy
• Drug dependence
• Neuropsychiatric disturbances : Schizophrenia, bipolar
disorders
• Pain
• Decreasing the brain damage following stroke / head injury.

25. As general anaesthetics
• Nitrous oxide, Cyclopropane and Xenon are
potent and selective inhibitors of NMDA-
activated currents apart from their action on
two pore K+ channels in producing the
anesthesia.

26. Felbamate Topiramate Zonisamide
Mechanism of
action
Inhibits NMDA
receptors
Potentiates
GABA effect
Inactivate Na+
channels,
↑GABA, opens K+
channels
Inhibits T type
Ca+2 channels,
inactivate Na
channels
Adverse effects Aplastic
anemia
hepatotoxicity
somnolence,
ataxia, anorexia,
nervousness,
fatigue
Metabolic acidosis
Uses Lennox-Gestaut
syndrome
Partial seizures
GTCS
Adjunctive in
partial seizures
Adjunctive in
partial seizures

27. NMDA antagonists in Pain reduction
• Ketamine & Methadone have been shown to
improve the neuropathic pain and opioid
resistant pain.
• Weak NMDA antagonists like
dextromethorphan, memantine, amantidine
didn’t show consistent effect in reducing the
pain but have lesser adverse event profile.

28. Antagonist contd..
• Perampanel – introduced as anti epileptic drug
• Kainate receptor antagonist – NBQX, ACET

29. Perampanel
• Selective non competitive antagonist of AMPA
• Partial seizures, tonic clonic seizures
• t1/2 – 105 hours, 95% protein bound
• Excreted in feces (75%)
• ADR - Serious psychiatric and behavioral
changes

30. Herbal drugs acting on NMDA
Ginseng
Ginkgo biloba
Curcuma longa

31. Recent advances
• CX1739- phase 2 trial – for respiratory
depression
• MOA- GlyT1 inhibitor - > elevation of
extracellular glycine levels through out the
brain.
• Preliminary study with LY2140023 (agonist at
glutamate receptor) is also been tried
• Glycine agonists : d-serine, and d-cycloserine