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Gaba modulators

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Gaba modulators

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Gaba modulators

  1. 1. GABA MODULATORS By Dr .Elza Joy Munjely, JR II, Govt. Medical College ,Kottayam.
  2. 2. Introduction • Gamma Amino Butyric Acid (GABA) - major inhibitory neurotransmitter of the mammalian CNS.
  3. 3. Inhibitory neurotransmitters • GABA • Glycine
  4. 4. The GABA system - target of a wide range of drugs active on the CNS- • Anxiolytics , • sedative-hypnotics, • General anesthetics, and • Anticonvulsants
  5. 5. Discovery • In 19th century – was known as a metabolite of plant and microorganisms • In early 20th century - was isolated as an amino acid in the brain of mouse through paper chromatography. • In 1950 Robert and Frankel discovered GABA in human brain.
  6. 6. Biosynthesis, Storage and Release
  7. 7. Synthesis
  8. 8. Glutamine Glutamate GABA Succinyl semialdehyde Glutaminase GAD GABA transaminase
  9. 9. Termination • Reuptake into presynaptic terminals and/or surrounding glial cells is the primary mechanism of termination.
  10. 10. RECEPTORS
  11. 11. THREE MAJOR TYPES I. GABA A II.GABA B III.GABA C
  12. 12. GABA A GABA B Type Ionotropic Metabotropic Location Widely spread ,mainly GABA ergic interneurons Widespread,presynaptic & postsynaptic Subcellular event Postsynaptic inhibition by ↑ chloride influx Presynaptic inhibition by ↓ calcium entry Postsynaptic inhibition by ↑Potassium efflux Agonist GABA,Muscimol,Gaboxadol,B ZD,Barbiturates,Steroid anaesthetics GABA,Baclofen Antagonist Bicuculline,Gabazine,Flumaze nil 2- hydroxy-saclofen Channel blocker Picrotoxin NA
  13. 13. GABA A RECEPTORS • Ligand gated ion channel • Distributed throughout the brain. • It is a heteropentamer, made of five subunits . • Ligand binds at the interface between α and β domain ( 2 α,2 β,1 γ)
  14. 14. • Different types of GABA A receptors present- depending on the type of subunit . • Subunits – alpha(1-6), beta(1-3), gamma(1-3), delta, epsilon, pi, theta and rho. • Different types of GABA A receptors - present in different regions of the brain , at different levels of development.
  15. 15. GABA A receptor when activated, an increase in the conductance. Increase in the influx of Cl- ions causing membrane hyperpolarization. Increase in the threshold for generating action potential. Inhibitory action
  16. 16. • Allosteric modulation The site where modulators bind is different from the site of binding of GABA agonist – known as “allosteric” site . Modulator - “allosteric modulator”. The modulator has no activity of its own. • Positive Allosteric Modulation: ligand binds allosteric site and enhance the action of neurotransmitter. E.g.BZD • Negative Allosteric Modulation: ligand binds to the allosteric site while an agonist is also bound and the channel opens less frequently. E.g. Bicuculline.
  17. 17. • G-protein coupled receptor. • Dimer of two, seven transmembrane spanning subunits held together by a coil – coil interaction btw their C- terminal tails. • Activation of receptors occurs when GABA binds to the extracellular domain of the B1 subunit which produce an allosteric change in the B2 subunit which couples to the G- protien • Widely distributed throughout the CNS. GABA B RECEPTORS
  18. 18. • Located both pre- and post-synaptically. • Presynaptically- auto-receptor. Inhibits voltage gated calcium channels,thus decrease neurotransmitter release. • Postsynaptically – inhibitory – long lasting hyperpolarization by activating K+ channel.
  19. 19. • Transmitter gated chloride channel • Retina,spinal cord,superior colliculus,pituitary • Physiological role is not yet discovered. GABA C RECEPTORS
  20. 20. DRUGS ACTING ON GABA RECEPTORS
  21. 21. DRUGS ACTING ON GABA A RECEPTORS Drugs Action GABA Endogenous agonist→promotes chloride influx Muscimol Agonist at GABA A site Bicuculline competitive anta gonist at GABA A binding site Picrotoxin Blocks chloride channel noncompetitively;acts on picrotoxin sensitive site Barbiturate Agonist at allosteric site,prolong GABA action,open chloride channel Alcohol, Inhalational anaesthetics,Propo fol Open chloride channel directly,Allosteric facilitation of GABA Benzodiazepine Agonist at allosteric BZD site→facilitate GABA action β -carboline Inverse agonist at BZD site→impede GABA action Flumazenil Competitive antagonist at BZD site
  22. 22. BENZODIAZEPINES • Powerful sedative,anxiolytic & anticonvulsant effect • Selective potentiation of GABA effect on GABA A receptors. • Binds to accessory site on GABA A receptor → facilitation of GABA binding • Binding of BZD → increases frequency of chloride channel opening -GABA facilitatory action
  23. 23. BARBITURATES • Binds to barbiturate binding site on GABA A chloride channel. • increase the lifetime of chloride channel opening induced by GABA → potentiate GABA ergic inhibition - GABA facilitatory action • At high conc. Barbiturates directly increase chloride conductance- GABA mimetic action • Enhance BZD binding to their receptors
  24. 24. DRUGS ACTING ON GABA B RECEPTORS Drug Action Baclofen Selective agonist 2-Hydroxy-saclofen Competitive antagonist γ-Hydroxybutyrate weak agonist
  25. 25. GABA Reuptake & Metabolism inhibitors Drug Action Tiagabine Inhibits GABA transporter(GAT 1) Vigabatrine Inhibits GABA transaminase Valproate Inhibits GABA transaminase,succinic semialdehyde dehydrogenase & stimulate Glutamic acid decarboxylase
  26. 26. Tiagabine Vigabatrin Valproate
  27. 27. Gabapentin & Pregabalin • Modify synaptic & nonsynaptic release of GABA • Bind to α2δ subunit of voltage gated N-type calcium channel → ↓calcium entry in the presynaptic membrane
  28. 28. THANKYOU

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