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GLUTAMATE RECEPTORS
Overview
• History
• Introduction
• Receptor types
• Role of the receptors
• Drugs acting at receptors – agonist and
antagonists
• Recent advances
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
Introduction
• In the CNS amino acids acting as
neurotransmitters (NT) are
Excitatory transmitter – Glutamate, Aspartate
Inhibitory transmitters – GABA, Glycine
Synthesis, storage and release of
glutamate
Glutamate Receptor Subtypes
• Act through
• Inotropic receptors (ligand gated ion channel)
• Metabotropic receptors
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)
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
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
Mechanism of LTP, LTD
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
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.
Piracetam
• Cyclic derivative of GABA
• Positive allosteric modulator of AMPA receptor
• Effect on NMDA receptor – learning and
memory
• Uses: dementia, depression and anxiety
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
Antagonists and negative modulators
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
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
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
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.
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.
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
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.
Antagonist contd..
• Perampanel – introduced as anti epileptic drug
• Kainate receptor antagonist – NBQX, ACET
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
Herbal drugs acting on NMDA
Ginseng
Ginkgo biloba
Curcuma longa
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

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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
  • 5.
  • 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
  • 10.
  • 11.
  • 12.
  • 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
  • 14.
  • 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
  • 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