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Drugs modifying GABA receptors
- 1. DRUGS MODIFYING GABA RECEPTORS Dr. K.Sathishbabu 2nd Year PG Department of Pharmacology
- 2. Overview • Introduction • Receptors • Drugs acting on Receptors • Recent advances • Summary • References 12/08/2019 2 DRUGS MODIFYING GABA RECEPTORS
- 3. Introduction • GABA – Gamma Amino Butyric Acid • Major inhibitory neurotransmitter of the mammalian brain • Others : Glycine 12/08/2019 3DRUGS MODIFYING GABA RECEPTORS
- 5. GABA Receptors 3 major types ;- • GABAA : ligand-gated Cl- ion channel; • GABA B : GPCR • GABA C : now considered as GABAA 12/08/2019 7 DRUGS MODIFYING GABA RECEPTORS
- 6. GABA A Receptors • Ionotropic receptors • Cys loop family Structure : • Pentameric • Transmembrane receptor • 5 subunits – around a central pore [α,β,ϒ] 12/08/2019 8 DRUGS MODIFYING GABA RECEPTORS
- 8. Distribution – • Postsynaptic membrane (CNS) • Others – leydig cells – immune cells – Liver & bone growth plates etc. Fast post-synaptic inhibition 12/08/2019 10 DRUGS MODIFYING GABA RECEPTORS
- 9. Mechanism of action Activation of GABAA receptor (Endogenous – GABA, Inositol; Exogenous - Drugs) ↓ Opening of central pore ↓ ↑ influx of Cl- ions through the pore ↓ Hyperpolarization of the neuronal membrane ↓ ↓ occurrence of Action potential ↓ Inhibition of neurotransmission 12/08/2019 11 DRUGS MODIFYING GABA RECEPTORS
- 10. Allosteric modulation : • “Allosteric modulator” - has no activity of its own. • Binds to a site other than that of GABA – “Allosteric site” • Positive Allosteric Modulation: ↑ the action of neurotransmitter. E.g.BZDs • Negative Allosteric Modulation: ↓ the action of neurotransmitter E.g. Bicuculline. 12/08/2019 12 DRUGS MODIFYING GABA RECEPTORS
- 11. GABA B Receptors • Metabotropic receptors • Coupled to G proteins – inhibit Ca2+ channels – activate K+ channels • Distribution : Central & Autonomic division of PNS 12/08/2019 13 DRUGS MODIFYING GABA RECEPTORS
- 12. • Presynaptically – as Autoreceptor Inhibits voltage-gated Ca2+ Channels ↓ ↓ neurotransmitter release • Postsynaptically – inhibitory activates K+ channels ↓ long-lasting hyperpolarization Slow post-synaptic inhibition 12/08/2019 14 DRUGS MODIFYING GABA RECEPTORS
- 13. Structure : • Dimeric • 2 transmembrane domains: GABA B1 & GABAB2 12/08/2019 15 DRUGS MODIFYING GABA RECEPTORS
- 14. Mechanism of action Binding of GABA to the extracellular domain of B1 ↓ Allosteric change in the B2 subunit (coupled to G protein) ↓ Inhibit adenylyl cyclase Activate K+ channels ↓ Ca2+ conductance ↓ ↓ 𝐍eurotransmitter release & Action potential 12/08/2019 16 DRUGS MODIFYING GABA RECEPTORS
- 15. DRUGS ACTING ON GABA RECEPTORS
- 16. Drugs acting on GABA A Receptors RECEPTOR SITE MODULATORY SITE AGONISTS Muscimol, Gaboxodol(THIP), Acamprosate, Isoguvacine, Progabide BZDs, Barbiturates, Ethanol, Steroid & inhaled anaesthetics, Neuroactive steroids, Topiramate, Non-BZDs, Quinazolinones ANTAGONISTS Bicuculline, Gabazine Flumazenil, Amentoflavone, INVERSE AGONISTS β carbolines CHANNEL BLOCKERS Picrotoxin, Cicutoxin, Pentylenetetrazole12/08/2019 18 DRUGS MODIFYING GABA RECEPTORS
- 17. Agonists Muscimol : - naturally occurring GABA analog - Amanita muscaria (hallucinogenic mushroom) - potent and specific agonist at GABAA receptors - widely used to study pharmacology of GABAA receptors Gaboxadol (THIP) : - synthetic analog of GABA & Partial agonist - Hypnotic (withdrawn)12/08/2019 19 DRUGS MODIFYING GABA RECEPTORS
- 18. Acamprosate : • GABA analogue • Partial GABAA agonist & weak NMDA-receptor antagonist • ↑ GABAA action (opens Cl- channels without GABA) • To treat alchohol dependence 12/08/2019 20 DRUGS MODIFYING GABA RECEPTORS
- 19. Benzodiazepines : • Sedative-hypnotic, Anxiolytic & Anti-convulsant • Allosteric modulators of GABAA receptors • bind to an ‘accessory’ site “Benzodiazepine binding site” • Ligands acting at this site Positive modulators Negative modulators (Agonists) (Inverse agonists)12/08/2019 21 DRUGS MODIFYING GABA RECEPTORS
- 20. Mechanism - GABA facilitatory action 12/08/2019 22 DRUGS MODIFYING GABA RECEPTORS
- 21. Barbiturates : • Centrally acting depressants – anticonvulsant & anaesthetic. Eg. Phenobarbitone, Pentobarbital etc. • Also GABA facilitators - ↑ the duration of the GABA gated chloride channel openings. (@low conc) • @high concentrations (anaesthetic)GABAmimetic, directly activating chloride channels • @very high concentrations – inhibitory effect12/08/2019 23 DRUGS MODIFYING GABA RECEPTORS
- 22. • Less selective than BZDs. - also ↓ the actions of glutamic acid (via binding to the AMPA receptor) • exert non-synaptic membrane effects. • Multiple sites of action - more pronounced central depressant effects • low margin of safety 12/08/2019 24 DRUGS MODIFYING GABA RECEPTORS
- 23. Alchohol : • Positive modulator of GABAA receptor (Extrasynaptic) • δ subunit- containing GABAA receptor – sensitive to low concentrations of ethanol Prolonged ethanol consumption ↓ δ subunit expression in the brain 12/08/2019 25 DRUGS MODIFYING GABA RECEPTORS
- 24. General anaesthetics : • GABAA receptors are the major site of action • IV anaesthetics: Etomidate, Propofol, Barbiturates & Neuroactive steroids • Volatile anaesthetics: Isoflurane and Enflurane --- --> multiple targets (GABAA being 1 of them) - @clinical(anaesthetic)doses : positive modulators - @higher doses : direct activators 12/08/2019 26 DRUGS MODIFYING GABA RECEPTORS
- 25. Neurosteroids : • Compounds related to steroid hormones - Metabolites of Progesterone & Androgens - act like BZDs: ↑ activation of GABAA receptors • δ subunit Anxiolytic, analgesic, anticonvulsive, sedative and hypnotic effects & GA (@high doses) • Acts on NMDA, AMPA, glycine, serotonin & nicotinic Ach receptors 12/08/2019 27 DRUGS MODIFYING GABA RECEPTORS
- 26. Alphaxolone : - Synthetic neurosteroid - developed as an anaesthetic agent. - potential benefits in the treatment of anxiety, epilepsy etc Negative modulators of GABAA : • Sulphated endogenous steroids - Pregnenolone sulphate & DHEAS 12/08/2019 28 DRUGS MODIFYING GABA RECEPTORS
- 27. Antagonists Bicuculline : - convulsant alkaloid - competitive antagonist at GABA-binding site - blocks fast inhibitory synaptic potential Gabazine : - Synthetic GABA analogue - Action similar to that of bicuculline Useful experimental tools - no therapeutic uses.12/08/2019 29 DRUGS MODIFYING GABA RECEPTORS
- 28. Flumazenil : • Synthetic BZD derivative (imidazobenzodiazepine) • Specific antagonist at BZD-binding site • Competitively antagonizes the binding of BZDs & Non-BZD hypnotics • Does not antagonize barbiturates, ethanol • Used to reverse the effects of benzodiazepine overdosage 12/08/2019 30 DRUGS MODIFYING GABA RECEPTORS
- 29. Inverse agonists • Drugs that bind to BZD site & exert the opposite effect to that of conventional BZDs Eg. β carbolines (βCCE) • BZD receptor exists in 2 distinct conformations: A - One which can bind GABA molecules & open the Cl- channel. B - One which cannot bind GABA. 12/08/2019 31 DRUGS MODIFYING GABA RECEPTORS
- 30. Direct Channel blockers • Picrotoxin - plant product ; convulsant - directly blocks Cl- channels of GABAA receptors - no therapeutic uses • Pentylenetetrazol (experimental convulsant), • TPBS (cage convulsant) 12/08/2019 32 DRUGS MODIFYING GABA RECEPTORS
- 31. Penicillin : • blocks the channel by interacting with the positively charged amino acid residues within the channel pore 12/08/2019 33 DRUGS MODIFYING GABA RECEPTORS
- 32. Therapeutic potential of GABA A receptors Agonists • Insomnia – eg. BZDs • Anxiety disorders – eg. BZDs (Alprazolam) • Epilepsy – eg. BZDs, Barbiturates (Phenobarbitone) • Chronic muscle spasm & spasticity – eg. BZDs • General anaesthesia – eg. Etomidate, Enflurane, • Barbiturates (thiopentone), neuroactive steroids 12/08/2019 34 DRUGS MODIFYING GABA RECEPTORS
- 33. Contd.. • Pre-anesthetic medication – eg. BZDs • Alchohol withdrawal – eg. BZDs, Acamprosate • Analgesia (adjuvant) • Psychiatry – Mania, Schizophrenia • Depression (Alprazolam,Adinazolam) • Post-stroke patients 12/08/2019 35 DRUGS MODIFYING GABA RECEPTORS
- 34. Antagonist • BZD overdosage (Flumazenil) • Reversal of BZD anaesthesia • Excessive day time Sleepiness Inverse agonists • Depression – β carbolines • Cognitive impairment 12/08/2019 36 DRUGS MODIFYING GABA RECEPTORS
- 35. Drugs acting on GABA B receptor AGONISTS POSITIVE MODULATORS ANTAGONISTS Baclofen GHB (ϒ-hydroxy butyrate) Others: Lesogaberan, Phenibut, Isovaline, SKF-97541 BHFF, Fasoracetam, BSPP Saclofen, Phaclofen, 2-OH saclofen, Homotaurine, CGP-35348 12/08/2019 37 DRUGS MODIFYING GABA RECEPTORS
- 36. Baclofen • Selective GABA B agonist • Structural analog of GABA • Used as a muscle relaxant – spasticity & skeletal muscle rigidity • Also in drug dependence • A/E - sedation, weakness,ataxia, can aggravate absence seizures 12/08/2019 38 DRUGS MODIFYING GABA RECEPTORS
- 37. Antagonists • Saclofen, 2-OH saclofen, CGP-35348 etc • Produce only minimal effects on CNS function • Main effect – Anti-epileptic action (in animal models of absence seizures) - Enhanced cognitive performance • Therapeutic use in humans not proven as yet. 12/08/2019 39 DRUGS MODIFYING GABA RECEPTORS
- 38. OTHERS Vigabartin Inhibit GABA transaminase Neuronal concentration of GABA Tiagabine Inhibit GABA uptake transporter[GAT] Inhibits GABA uptake GABA availability 12/08/2019 DRUGS MODIFYING GABA RECEPTORS 40
- 39. Valproic acid Inhibit GABA reuptake by GAT inhibition Activates GAD 12/08/2019 DRUGS MODIFYING GABA RECEPTORS 41
- 40. RECENT ADVANCES • Newer target for – Alzheimer’s disease – Parkinsonism etc. • Effect on Cardiovascular system 12/08/2019 42 DRUGS MODIFYING GABA RECEPTORS
- 43. REFERENCES 1) The Pharmacological basis of therapeutics – Goodman & Gilman ; 13th edition 2) Basic & Clinical Pharmacology – Katzung & Trevor 3) Rang & Dale’s Pharmacology 4) Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition: GABA Receptor Physiology and Pharmacology - Richard W Olsen and Timothy M DeLorey 12/08/2019 DRUGS MODIFYING GABA RECEPTORS 45
- 44. • 5) Jembrek MJ, Vlainic J. GABA Receptors: Pharmacological Potential and Pitfalls.Curr Pharm Des. 2015;21(34):4943-59. • 6) Johnston GA, Chebib M, Hanrahan JR, Mewett KN. GABA(C) receptors as drug targets. Curr Drug Targets CNS Neurol Disord. 2003 Aug;2(4):260-8. 12/08/2019 DRUGS MODIFYING GABA RECEPTORS 46
- 45. THANK YOU
Editor's Notes
- Present mainly in human brain & little amount in periphery.
- It is primarily synthesized from glutamate by enzyme GAD
- GABA is more selective to GABAC (than GABAA) Found in – retina,spinal cord,superior colliculus,pituitary Pentamer of ρ subunits with Cl- channel in the centre (GABAρ)
- (also glycine, nicotinic & 5-HT3 receptors)
- (‘Venus fly trap’)
- Tetra hydro isoxazolo pyridine
- Etomidate & Propofol – selective for α2 & α3 subunits
- Mechanism explained by Two-state model