This document discusses glutamate receptors, including their history, types, roles, and drugs that act on them. It notes that glutamate is the major excitatory neurotransmitter in the central nervous system. There are two main types of glutamate receptors: ionotropic receptors which are ligand-gated ion channels including NMDA, AMPA, and kainate receptors, and metabotropic G protein-coupled receptors divided into groups 1, 2, and 3. The roles of glutamate receptors include synaptic plasticity, learning and memory, and excitotoxicity. Many drugs have been developed that act as agonists or antagonists at glutamate receptors and are being investigated for conditions like Alzheimer's, Parkinson

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