This document provides an overview of glutamate and GABA, their receptors and therapeutic applications. It discusses the synthesis, storage, release and termination of glutamate and GABA in the central nervous system. It describes the ionotropic and metabotropic glutamate receptors and GABAA and GABAB receptors. It also discusses conditions associated with glutamate like seizures, neurodegenerative diseases and stroke. Finally, it outlines current and upcoming therapeutic agents that target glutamate and GABA receptors and their uses, mechanisms and adverse effects.

1. GLUTAMATE & GABA
RECEPTORS AND
THERAPEUTIC APPLICATIONS

2. OUTLINE
• INTRODUCTION
• HISTORY
• GLUTAMATE :
Synthesis, storage, release, termination
Glutamate receptors
Synaptic plasticity, ltp/ltd, excitotoxicity
Therapeutic applications & upcoming agents
• γ-AMINO BUTYRIC ACID:
Synthesis, storage, release, termination
Gaba receptors
Therapeutic applications
• CONCLUSION

3. INTRODUCTION: AMINO ACID TRANSMITTERS
•CNS- high concentrations of certain amino acids.
•Dicarboxylic vs Monocarboxylic amino acids.
•Terms : Neurotransmitters vs Neuromodulators.

4. HISTORY
•1950s - little reason to look further.
•γ-aminobutyric acid (GABA) - (1950s) transmitter role
postulated.
•Curtis’s group - glutamate produced a strong excitatory
effect.
•1960s - GABA and excitatory amino acids (EAAs) ? Mere
pharmacological curiosities.
•1970s – Glycine.
•Discovery of EAA antagonists.

5. GLUTAMATE
•Synthesis
•Storage
•Release
•Termination of Action

8. GLUTAMATE RECEPTORS
• IONOTROPIC GLUTAMATE RECEPTORS
• 4 subunits assembly, each with ‘pore loop’.
• 16 different receptor subunits –
IUPHAR recommended terminology.
• NMDA receptors - 7 types of subunits (GluN1, GluN2A,
GluN2B, GluN2C, GluN2D, GluN3A, GluN3B).
•AMPA receptors – 4 types of subunits (GluA1–4).
• Kainate receptors – 5 types of subunits (GluK1–5).

9. •Receptors comprising different subunits; differ in
characteristics, e.g. AMPA receptors lacking GluA2.
•NMDA – slow excitatory. AMPA, kainate receptors - fast
excitatory.
•NMDA and Kainate receptors – also pre-synaptic.
•Cortex, basal ganglia and sensory pathways.
•NMDA, AMPA – generally co-localised.

10. NMDA receptors:
Special features
•Highly permeable to
Ca2+.
•Mg2+.
•Glutamate +
simultaneous
depolarization
(AMPA/kainate).
•Role of glycine.

13. •METABOTROPIC GLUTAMATE RECEPTORS
•8 different metabotropic glutamate receptors (mGlu1–8).
•Divided into three groups.
•Group 1 mGlu receptors located post-synaptically and
are largely excitatory.
•Group 2 and 3 mGlu receptors presynaptic receptors ↓
synaptic transmission and neuronal excitability.

15. SYNAPTIC PLASTICITY & LONG-TERM
POTENTIATION (LTP)
•NMDA, mGlu receptors – Long term adaptive changes.
•Long-term potentiation : prolonged enhancement of
synaptic transmission following presynaptic stimulation.
•Counterpart - long-term depression (LTD).

18. EXCITOTOXICITY
•High concentrations of glutamate → neuronal cell death.
•Glutamate-mediated excitotoxicity may underlie the
damage occurring after ischemia or hypoglycemia in
the brain.
•NMDA receptor antagonists.
•? Etiology of chronic neurodegenerative diseases.

20. DISEASE ASSOCIATIONS WITH GLUTAMATE
Seizures
ADHD
Autism
Neurodegenerative diseases
 Multiple Sclerosis
 Rasmussen’s Encephalitis
 Stroke

21. THERAPEUTIC APPLICATIONS
KETAMINE
•Congener of Phencyclidine.
•MOA : NMDA channel blocker and …
•Uses : “Dissociative Anesthesia” (hypotensive. Asthmatic.
Pediatric procedures)
•A/E : Hallucinations, Emergence Delirium, Amnesia, ↑ ICT,
↑ HR, Nausea, Vomiting, ↑IOP, Erythema, Rash.

22. MEMANTINE
•NMDA Channel blocker, ↓ excitotoxicity.
•Uses : Moderate to Severe Alzheimer’s Disease.
•A/E : Confusion, Dizziness, Drowsiness, Headache,
insomnia, agitation.
FELBAMATE
•NMDA Blocker, +ve modulation of GABA-R.
•Uses : Severe Refr. Partial Seizures, Lennox-Gastaut Syn.
•A/E : ↓ appetite, vomiting, headache, aplastic anemia,
liver failure.

23. TOPIRAMATE
•AMPA-kainate antag.
•Uses : Initial monotherapy & adj. therapy for partial onset/
primary GTCS, L-G Syndr, Migraine.
•A/E : Fatigue, Weight loss, nervousness, renal calculi.
ACAMPROSATE
•Alcoholism. A/E – Diarrhea, allergy, headache, insomnia.
RILUZOLE
•Amyotrophic Lateral Sclerosis.
•Modest ↑ in survival.

24. UPCOMING AGENTS
•Analgesic : TEZAMPANEL : AMPA-Kainate Antagonist ;
Phase III (Ac. Migraine)
•ALS : TALAMPANEL : AMPA Antag. ; ALS negative results.
•Seizure Disorder: PERAMPANEL : AMPA Antag. ;
FDA – 2012 but role unclear.
A/E – Suicidal thoughts,
dizziness, vertigo,
aggression, slurred
speech, abuse liability.

25. • Stroke: NBQX : AMPA-Kainate Antag ; Pre Clinical
TRAXOPRODIL : NMDA Antag. ; QT prolongation.
• Neurodegen. RADIPRODIL :NMDA Antag.; Pre-Clin (Parkinson’s)
REMACEMIDE:NMDA Antag.;Huntington(III),Park(II)
FARAMPATOR : AMPA + modulator ; Alzheimer’s (I)
PIRACETAM : Ampakine ; Dementia, not approved.

26. γ-AMINOBUTYRIC ACID
•Synthesis
•Storage
•Release
•Termination of Action

29. GABA RECEPTORS
GABAA (IONOTROPIC) RECEPTORS
• IUPHAR Recommendation for
GABAC.
• Pentamers; 19 different subunits :
(α1–6, β1–3, γ1–3, δ, ε, θ, π and ρ1–3).
• α1β2γ2 - the most abundant.
• α-β-α-β-γ

32. GABAB (METABOTROPIC) RECEPTORS
•Gi - inhibit adenylyl cyclase, activate K+ channels, and
reduce Ca2+ conductance.

34. THERAPEUTIC APPLICATIONS
Drug/ Class Mechanism Use Adverse Effects
BARBITURATES ↑ Duration GABAA
gated Chloride
Channel
Anesthesia,
Anticonvulsant,
hyperbilirubinemia,
Sedative-Hypnotics
Distortion of Sleep Architecture, Learning and
Memory impairment, respiratory depression,
abuse, laryngeal edema, hypersensitivity.
BENZODIAZEPINES ↑ Frequency
GABAA gated
Chloride Channel
Anxiety, Insomnia,
Induction, Sk
muscle relaxation,
Anticonvulsant, Alc
Withdrawal
Drowsiness, fatigue, disorientation, lethargy,
respiratory depression, abuse, impaired
memory and learning, date rape
Z-DRUGS Agonist at
modulatory site at
GABAA R to which
BZD bind
Insomnia Rebound insomnia, hangover are less.
Headache, daytime drowsiness, nightmares at
high doses.

35. Drug/ Class Mechanism Use Adverse Effects
ETOMIDATE GABAA
Agonist
Induction of
Anesthesia
Nausea, Vomiting, Suppression
of corticosteroid synthesis, Pain
on injection, seizures.
PROPOFOL GABAA
Agonist
Induction and
maintenance,
status epi
Irregular heart rate,
Hypotension, Burning sensation
at site of injection, Apnea,
seizures, addiction, Propofol
Infusion Syndrome (PRIS).
FLUMAZENIL Selective BZD
Receptor
Antagonist
Suspected
BZD overdose,
reversal
of sedative
effects
Convulsions , dizziness, injection
site pain, increased sweating,
headache, visual disturbances.

36. Drug/ Class Mechanism Use Adverse Effects
BACLOFEN GABAB Agonist Spastic
movement
disorders
Vomiting, sedation,
respiratory depression,
seizures, Withdrawal
syndrome, abuse potential.
TIAGABINE GABA
Reuptake
Inhibitor
Adj. t/t of
partial seizures
Dizziness, memory imp.,
tremor, headache,
diarrhea, depression
VALPROATE GABA
Transaminase
Inhibitor
Epilepsy, Psy.
Disorders,
Migraine
Wt gain, alopecia, tremors,
hepatic necrosis,
pancreatitis, NTD.
VIGABATRIN GABA
Transaminase
Inhibitor
Infantile Spasm Retinal atrophy, confusion,
fatigue, wt gain, diarrhea,
irritability.

37. PREGABALIN
&
GABAPENTIN
GABA
analogues
Partial seizures (in addn. to
other drugs), Neuropathic pain
Drowsiness,
dizziness,
ataxia,
fatigue.

38. CONCLUDING REMARK

39. THANK YOU