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/ADRKynureneic acid

Antagonist at glycine binding site Antiexcitotoxic, anticonvulsant

Ketamine Non competitive antagonist at NMDAIM: 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, epilepsyADR: 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, glaucoma10–30 mg/dayADR: confusion, hypertonia, cystitis

DRUG MOA USES/DOSE/ADR

Riluzole Presynaptically inhibits glutamate release Post synaptically blocks postsynaptic NMDA- and kainate-type glutamate receptors andinhibits voltage-dependent Na+ channels.

Amyotrophic lateral sclerosisPO: 50mg BDADR: dizziness, weight loss

Amantadine Blocks NMDA glutamate receptors Parkinson's disease (neurotoxicity, dyskinesia)PO: 100–200mg/dayADR: 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 agentPO: 10 mg TDS

Methadone NMDA receptor antagonist 2.5-10mg q8-12th hourlyADR: sedation, fatigue

Acamprosate Weak antagonist of NMDA receptors, activator of GABAA receptors

Anticraving drugADR: 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 NMDAreceptorsPotentiatesGABA effect

Inactivate Na+ channels,↑GABA, opens K+ channels

Inhibits T type Ca+2 channels,inactivate Na channels

Adverse effects Aplasticanemiahepatotoxicity

somnolence, ataxia, anorexia,nervousness, fatigue

Metabolic acidosis

Uses Lennox-Gestaut syndromePartial seizuresGTCS

Adjunctive inpartial seizures

Adjunctive inpartial 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