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Gaba receptors & drugs acting on them
- 1. - Dr. Chandini Rao - Moderator: Dr. Princy Pallatty 1
- 2. Overview 2 Introduction GABA receptors: GABA A receptors GABA B receptors GABA C receptors Drugs acting on GABA receptors – Agonists Modulators Antagonists
- 3. Introduction Gamma Amino Butyric Acid (GABA) - major inhibitory neurotransmitter of the mammalian brain Others – Glycine (spinal cord & brain stem) 3
- 4. Discovery 4 19th century – was known as a metabolite of plant & microorganisms Early 20th century - isolated as an amino acid in the brain of mouse through paper chromatography. 1950 - Robert and Frankel discovered GABA in human brain.
- 5. Synthesis, Storage & Function 5
- 6. 6 Glutamine Glutamate Succinyl semialdehyde Succinic acid GABA Glutaminase GAD GABA transaminase Vigabatrine
- 7. 7
- 8. Termination – Reuptake into presynaptic terminals and/or surrounding glial cells via reuptake transporters (GAT) Function – Inhibitory neurotransmitter in the brain (cerebellar purkinje neurons, cerebellar cortex, sunstantia nigra, globus pallidus etc) - 20% of CNS neurons - GABAergic - 30% of all the synapses Presynaptic inhibition within the spinal cord 8
- 10. 10 3 major types – GABAA : ligand-gated Cl- ion channel; GABA B : GPCR GABA C : transmitter-gated Cl- ion channel
- 11. GABAA Receptor Ionotropic receptors Cys loop family (also glycine, nicotinic & 5-HT3 receptors) Distribution – Postsynaptic membrane (CNS) Other – leydig cells immune cells liver bone growth plates etc11
- 12. 12 • Fast postsynaptic inhibition • Selectively permeable to Cl− ions • Site of action of Benzodiazepines Barbiturates Ethanol Anaesthetic steroids Volatile anaesthetics
- 13. Structure 13 Pentameric Transmembrane receptor 5 subunits – around a central pore. 2 α1, 2 β1 & 1 ϒ2 subunits (most common) Other – α2, α3 & α5 (BZDs)
- 14. 14
- 15. Mechanism of action 15 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 neurotransmition (early part of IPSP)
- 16. 16 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.BZD Negative Allosteric Modulation: ↓ the action of neurotransmitter E.g. Bicuculline.
- 17. GABAB Receptor 17 • Metabotropic receptors • Coupled to G proteins inhibit Ca2+ channels activate K+ channels • Distribution – Central & Autonomic division of PNS
- 18. 18 • Presynaptically – as Autoreceptor - inhibits voltage-gated Ca2+ channels ↓ ↓ neurotransmitter release • Postsynaptically - inhibitory - activates K+ channels ↓ long-lasting hyperpolarization - Slow post-synaptic inhibition
- 19. Structure 19 • Dimeric - 2 transmembrane domains: GABAB1 & GABAB2
- 20. Mechanism of action 20 Binding of GABA to the extracellular domain of B1 ↓ Allosteric change in the B2 subunit (coupled to G protein) (‘Venus fly trap’) ↓ Inhibit adenylyl cyclase Activate K+ channels ↓ Ca2+ conductance ↓ ↓ 𝐍eurotransmitter release & Action potential
- 21. GABAC Receptor 21 Least studied among the 3 major classes of GABA receptors 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)
- 22. 22
- 23. 23 GABA A GABA B Type Ionotropic Metabotropic Location Widespread; Post-synaptic Widespread; Pre- & Post-synaptic Structure Pentamer Dimer MOA Post-synaptic inhibition by - ↑ Cl- influx Pre-synaptic inhibition by – ↓ Ca2+ entry Post-synaptic inhibition by – ↑ K+ permeability Endogenous agonist GABA GABA
- 24. 24 GABA A GABA B Pharmacological effects Sedation Hypnosis Anxiolysis Anticonvulsant Amnesia Muscle relaxation Euphoria Central muscle relaxation Epileptogenesis Suppression of drug craving Antinociception Cognitive impairment Inhibition of hormone release
- 25. Drugs acting on GABA Receptors 25
- 26. Drugs acting on GABA A Receptor 26 Receptor site Modulatory site Agonists Muscimol, Gaboxodol (THIP), Acamprosate, Isoguvacine, Progabide BZDs, Barbiturates, Ethanol, Steroid & inhaled anaesthetics, Neuroactive steroids, Topiramate, Non-BZDs (Zolpidem, Zaleplon Eszopiclone), Quinazolinones Partial agonists
- 27. 27 Receptor site Modulatory site Antagonists Bicuculline, Gabazine Flumazenil, Amentoflavone, Inverse agonist β carbolines Channel blockers Picrotoxin, Cicutoxin, Pentylenetetrazole
- 28. 28
- 29. Agonists 29 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 at GABAA - hypnotic (withdrawn)
- 30. Benzodiazepines 30 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 (Agonists) Negative modulators (Inverse agonists)
- 31. Mechanism - GABA facilitatory action 31
- 32. 32
- 33. 33 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) - may also be GABAmimetic, directly activating chloride channels • @very high concentrations – inhibitory effect
- 34. 34 • Less selective than BZDs. - also ↓ the actions of glutamic acid (via binding to the AMPA receptor) • also exert nonsynaptic membrane effects. • Multiple sites of action more pronounced central depressant effects low margin of safety
- 35. General anaesthetics 35 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 Etomidate & Propofol – selective for α2 & α3 subunits
- 36. Neurosteroids 36 Compounds related to steroid hormones - metabolites of progesterone & androgens - act like BZDs: ↑ activation of GABAA receptors (& steroid receptors) δ subunit Anxiolytic, analgesic, anticonvulsive, sedative and hypnotic effects, & general anaesthesia (@high doses) Also act on NMDA, AMPA, glycine, serotonin & nicotinic Ach receptors
- 37. 37 Alphaxolone - Synthetic neurosteroid - developed as an anaesthetic agent. - potential benefits in the Rx of anxiety, epilepsy etc Negative modulators of GABAA : Sulphated endogenous steroids - Pregnenolone sulphate - DHEAS
- 38. Alchohol 38 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
- 39. 39 Acamprosate • GABA analogue • To treat alchohol dependence • Partial GABAA agonist & weak NMDA-receptor antagonist • In Chronic alchoholism – down-regulation of GABAA receptors little effect on AP unopposed sympathetic activation Alchohol withdrawal X ↑ GABAA action (opens Cl- channels w/o GABA)
- 40. Antagonists 40 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 but have no therapeutic uses.
- 41. Flumazenil 41 Synthetic BZD derivative (imidazobenzodiazepine) Specific antagonist @ BZD-binding site (modulatory site) Competitively antagonizes the binding of BZDs & Non-BZD hypnotics Does not antagonize barbiturates, meprobamate & ethanol Used to reverse the effects of benzodiazepine overdosage
- 42. Inverse agonists 42 Drugs that bind to BZD site & exert the opposite effect to that of conventional BZDs Eg. β carbolines (βCCE), diazepam-binding inhibitor Mechanism explained by Two-state model - BZD receptor exists in 2 distinct conformations: A - One which can bind GABA molecules & open the Cl- channel. B - One which cannot bind GABA.
- 43. 43 BZD agonists A Inverse agonists Antagonists A & B B
- 44. Direct Channel blockers 44 Picrotoxin - plant product - convulsant - directly blocks Cl- channels of GABAA receptors - no therapeutic uses Pentylenetetrazol (experimental convulsant), TPBS (cage convulsant) Penicillin – blocks the channel by interacting with the positively charged amino acid residues within the channel pore
- 45. Therapeutic potential of GABAA receptors 45 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 Pre-anesthetic medication – eg. BZDs Alchohol withdrawal – eg. BZDs, Acamprosate
- 46. 46 Agonists (contd) Potential uses of BZDs– Analgesia (adjuvant) Psychiatry – Mania, Schizophrenia Depression (Alprazolam,Adinazolam) Post-stroke patients Antagonist (Flumazenil) BZD overdosage Reversal of BZD anaesthesia Excessive day time sleepiness Inverse agonists Depression – β carbolines Cognitive impairment
- 47. Drugs acting on GABA B receptor 47 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
- 48. Baclofen 48 Selective GABAB agonist Structural analog of GABA Used as a muscle relaxant – spasticity & skeletal muscle rigidity Also in drug dependence S/E - sedation, weakness, ataxia, can aggravate absence seizures (not used in epilepsy)
- 49. 49 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.
- 50. Drugs acting on GABAC receptor 50 Tried in Rx of visual, sleep and cognitive disorders (THIP & CGP-36742) 4 agents – Selective agonists Selective antagonists CACA (Cis-4-aminocrotonic acid) CAMP (cis-2-aminomethyl cyclopropanocarboxylic acid) TPMPA (1, 2, 5, 6- tetrahydropyridine-4 methylphosphinic acid) 3-ACMPA (3-aminocyclopentyl methylphosphinic acid)
- 51. 51
- 52. 52 References: 1) The Pharmacological basis of therapeutics – Goodman & Gilman 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 - RichardW Olsen andTimothy M DeLorey 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 DrugTargets CNS Neurol Disord. 2003 Aug;2(4):260-8. Jembrek MJ, Vlainic J. GABA Receptors: Pharmacological Potential and Pitfalls. Curr Pharm Des. 2015;21(34):4943-59. Jembrek MJ, Vlainic J. GABA Receptors: Pharmacological Potential and Pitfalls. Curr Pharm Des. 2015;21(34):4943-59.
Editor's Notes
- Gamma Amino Butyric Acid (GABA) - major inhibitory neurotransmitter of the mammalian brain. In the spinal cord and brain stem, glycine is also important.
- Discovery – Although it had been shown to be in biological tissues as early as 1910, its presence in the CNS was not described until some 40 years later. Only after 1950, when the free amino acid was positively identified in mammalian brain, did interest in its potential neurochemical significance arise.
- GABA is formed from glutamate (Fig. 37.1) by the action of glutamic acid decarboxylase (GAD), an enzyme found only in GABA-synthesising neurons in the brain
- GABA can be destroyed by a transamination reaction in which the amino group is transferred to α-oxoglutaric acid (to yield glutamate), with the production of succinic semialdehyde and then succinic acid. This reaction is catalysed by GABA transaminase, an enzyme located primarily in astrocytes. It is inhibited by vigabatrine, another compound used to treat epilepsy
- GABAergic neurons and astrocytes take up GABA via specific transporters, thus removing GABA after it has been released. GABA transport is inhibited by guvacine, nipecotic acid and tiagabine. Tiagabine is used to treat epilepsy
- Reuptake into presynaptic terminals and/or surrounding glial cells is the primary mechanism of termination. GABA functions as inhibitory neurotransmitter in many pathways in the brain (cerebellar Purkinje neurons, cerebellar cortex, sunstantia nigra, globus pallidus etc) About 20% of CNS neurons are GABAergic; and GABA serves as a transmitter at about 30% of all the synapses in the CNS may also mediate presynaptic inhibition within the spinal cord.
- GABA receptors have been divided into three main types: A, B, and C. • The most prominent GABA- receptor subtype, the GABAA receptor, is a ligand- gated Cl− ion channel, an “ionotropic receptor.” • The GABAB receptor is a GPCR. • The GABAC receptor is a transmitter- gated Cl− channel.
- GABAA receptors are members of the Cys loop family of receptors that also includes the glycine, nicotinic, and 5-HT3 receptors primarily located postsynaptically and Distributed throughout the brain. GABAA receptors can also be found in other tissues, including leydig cells, placenta, immune cells, liver, bone growth plates and several other endocrine tissues.
- mediate fast postsynaptic inhibition, the channel being selectively permeable to Cl− GABA A –chloride macromolecular complex is 1 of the most versatile drug-responsive machines in the body. The GABAA receptor is the major molecular target for the action of many drugs in the brain
- GABAA receptor is a pentameric transmembrane receptor that consists of five subunits arranged around a central pore (typical for ionotropic Rs) Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly. Different types of GABA A receptors present- depending on the type of subunit A major isoform of the GABA A receptor (that is found in many regions of the brain) consists of two α1 subunits, two β2 subunits, and one γ2 subunit. (Cross-section) In this isoform, the two binding sites for GABA are located between adjacent α1 and β2 subunits, and the binding pocket for benzodiazepines (the BZ site of the GABAA receptor) is between an α1 and the γ2 subunit. However, GABAA receptors in different areas of the CNS consist of various combinations of the essential subunits, and the benzodiazepines bind to many of these, including receptor isoforms containing α2, α3, and α5 subunits.
- The distribution of different subunit combinations of GABAA and their functions in the mammalian brain are summarized in Table
- The ligand endogenous compound that causes this receptor to open; once bound to GABA, the protein receptor changes conformation within the membrane, opening the pore in order to allow chloride anions (Cl−) to pass down an electrochemical gradient. Upon activation, the GABAA receptor selectively conducts Cl− through its pore, resulting in hyperpolarization of the neuron. This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring. The net effect is typically inhibitory, reducing the activity of the neuron The GABAA channel opens quickly and thus contributes to the early part of the inhibitory post-synaptic potential (IPSP)
- Allosteric modulation The site where modulators bind is different from the site of binding of GABA – 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.
- Less is known about the GABAB receptor, primarily due to the limited number of pharmacological agents selective for this site. GABAB receptors (GABABR) are metabotropic class C GPC transmembrane receptors for gamma-aminobutyric acid (GABA) that are linked via G-proteins to potassium channels. GABAB receptors are metabotropic receptors These receptors are coupled to G proteins that, depending on their cellular location, either inhibit Ca2+ channels or activate K+ channels. GABAB receptors are found in the central as well as in the autonomic division of the peripheral nervous system.
- 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. This inhibitory postsynaptic potential is long-lasting and slow because the coupling of receptor activation to K+ channel opening is indirect and delayed
- Dimeric structure of the GABA B receptor. The receptor is made up of two seven-transmembrane domain subunits (GABA B1 R & GABA B2 R) held together by a coil/coil interaction between their C-terminal tails.
- Activation of the receptor occurs when GABA binds to the extracellular domain of the B1 subunit. This produces an allosteric change in the B2 subunit which is coupled to the G-protein. It is speculated that binding of GABA causes the subunits to swing shut around the agonist like a venus fly trap.[citation needed]
- The GABAC receptor is less widely distributed than the A and B subtypes. GABA is more potent by an order of magnitude at GABAC than at GABAA receptors, and a number of GABAA agonists (e.g., baclofen) and modulators (e.g., benzodiazepines and barbiturates) seem not to interact with GABAC receptors. GABAC receptors are found in the retina, spinal cord, superior colliculus, and pituitary GABAC receptors are the least studied of the three major classes of GABA receptors. it is thought that GABAρ subunits assemble into a pentamer that forms a Cl- channel in its center. There is evidence for functional GABA(C) receptors in the retina, spinal cord, superior colliculus, pituitary and gastrointestinal tract. Given the lower abundance and less widespread distribution of GABA(C) receptors in the CNS compared to GABA(A) receptors, GABA(C) receptors may be a more selective drug target than GABA(A) receptors. it is thought that GABAρ subunits assemble into a pentamer that forms a Cl- channel in its center
- Although GABA a sites generally outnumber GABA b sites
- anxiolytic, anticonvulsant, amnesic, sedative, hypnotic, euphoriant, and muscle relaxant properties. pharmacological effects of GABA b, including central muscle relaxation, epileptogenesis, suppression of drug craving, antinociception, cognitive impairment and inhibition of hormone release
- Muscimol, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridine-3-ol (THIP, a bicyclic muscimol analog) and isoguvacine are structural analogs of GABA, and have direct GABA mimetic effects,
- muscimol, a naturally occurring GABA analog isolated from the hallucinogenic mushroom Amanita muscaria. It is a potent and specific agonist at GABAA receptors Muscimol has been widely used as a valuable tool to study pharmacology of GABAA receptors, and was the lead compound in the development of a range of GABAergic agents A synthetic analogue, gaboxadol is a partial agonist that was developed as a hypnotic drug (Ch. 43) but has now been withdrawn
- Benzodiazepines and other substances acting at the benzodiazepine binding site are the most commonly prescribed drugs in therapeutic use due to their desirable anxiolytic, myorelaxant, sedative/hypnotic and anticonvulsant effects. Due to their pharmacological and clinical relevance, benzodiazepines have attracted much attention as allosteric modulators of GABAA receptors Various ligands acting at benzodiazepine binding site can enhance (positive modulators or agonists) or reduce (negative modulators or inverse agonists) the actions of GABA on GABAergic transmission with a different range of efficacy (from full to partial). Antagonists are devoid of intrinsic activity, but can inhibit effects of both positive and negative modulators
- They bind with high affinity to an accessory site (the ‘benzodiazepine receptor’) (b/w α1 & ϒ2 𝑠𝑢𝑏𝑢𝑛𝑖𝑡) on the GABAA receptor, in such a way that the binding of GABA is facilitated and its agonist effect is enhanced. Conversely, inverse agonists at the benzodiazepine receptor (e.g. Ro15-4513) reduce GABA binding The benzodiazepines do not substitute for GABA but appear to enhance GABA’s effects allosterically without directly activating GABAA receptors or opening the associated chloride channels. increases frequency of chloride channel opening -GABA facilitatory action thus accounting for their pharmacological and therapeutic actions
- The GABAA-chloride channel macromolecular complex is one of the most versatile drug-responsive machines in the body. In addition to the benzodiazepines there are Modulators that also enhance the action of GABA, but whose site of action is less well defined than that of benzodiazepines , include other CNS depressants such as barbiturates (Ch. 43), anaesthetic agents (Ch. 40) alcohol, Non-BZDs and neurosteroids. Barbiturates Barbiturates comprise another class of centrally acting depressants commonly used therapeutically for anesthesia and control of epilepsy. Phenobarbital and pentobarbital are two of the most commonly used barbiturates Barbiturates also facilitate the actions of GABA at multiple sites in the CNS, but—in contrast to benzodiazepines—they appear to increase the duration of the GABA-gated chloride channel openings. At high concentrations, the barbiturates may also be GABAmimetic, directly activating chloride channels. These effects involve a binding site or sites distinct from the benzodiazepine binding sites At low µM (sub-anesthetic) concentrations they potentiate GABA-induced effects (modulatory effect) and prolong duration of open conformation of chloride channel, possibly by stabilizing open state(s). In higher µM (anesthetic) concentrations (app. >50 µM) they directly open chloride channel (agonistic effect), whereas at very high mM concentrations block GABA-induced current (inhibitory effect)
- . Barbiturates are less selective in their actions than benzodiazepines, because they also depress the actions of the excitatory neurotransmitter glutamic acid via binding to the AMPA receptor. Barbiturates also exert nonsynaptic membrane effects This multiplicity of sites of action of barbiturates may be the basis for their ability to induce full surgical anesthesia (see Chapter 25) and for their more pronounced central depressant effects (which result in their low margin of safety) compared with benzodiazepines and the newer hypnotics.
- GABAA receptors are the major site of action of clinically used intravenous anesthetics such as etomidate, propofol, barbiturates and neuroactive steroids. On the other hand, clinically used volatile anesthetics such as isoflurane and enflurane, and long- chain alcohols, presumably act via a multitude of targets, GABAA receptors being just one of them. In general, (just like barbiturates) GABAA receptors are positively modulated by clinical doses of anesthetics, while at higher concentrations anesthetics can directly activate GABAA receptors etomidate and propofol (see Chapter 25) appear to act selectively at GABAA receptors that contain α2 and α3 subunits, the latter suggested to be the most important with respect to the hypnotic and muscle-relaxing actions of these anesthetic agents..
- Neurosteroids (see Lambert et al., 2003) are compounds that are related to steroid hormones but that act (like benzodiazepines) to enhance activation of GABAA receptors as well as on conventional intracellular steroid receptors. Interestingly, they include metabolites of progesterone and androgens that are formed in the nervous system, and are believed to have a physiological role. In general, they potently enhance function of synaptic and extrasynaptic GABAA receptors by an allosteric mechanism upon administration neurosteroids exert anxiolytic, analgesic, anticonvulsive, sedative and hypnotic effects, while applied at higher doses may induce a state of general anesthesia. mediated by extrasynaptic δ subunitcontaining GABAA receptors Although the most important effects of neurosteroids are mediated via GABAA receptors, also act on N-methyl-Daspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), kainate, glycine, serotonin, sigma type-1, and nicotinic acetylcholine receptors
- Synthetic neurosteroids include alphaxolone, developed as an anaesthetic agent. (potential therapeutics in the treatment of anxiety, epilepsy and other brain disorders) Neuroactive steroids may act both as positive and negative modulators of GABAA receptor function. sulphated endogenous steroids like pregnenolone sulphate and dehydroepiandrosterone sulphate (DHEAS) act as negative modulators at steroid binding site. sulfation at C-3 reverses the direction of modulation from positive to negative, suggesting that sulfation could be an important control point for the activity of endogenous neurosteroids
- Ethanol is often classified as positive modulator of GABAA receptor activity (like BZDs etc) potentiation of GABAA receptor function finding also suggests that extrasynaptic GABAA receptors are primary targets for ethanol y found that GABAA receptors responsive to these low concentrations require presence of δ-subunit, prolonged ethanol consumption that leads to the development of alcohol dependence induces changes of GABAA receptor subunits at transcriptional and translational levels in brain area-specific manner, including reduction in subunit expression in the orbitofrontal cortex, cerebellum, hippocampus and amygdala
- Acamprosate (N-acetylhomotaurine; CAMPRAL) is an analogue of GABA. used along with counselling to treat alcohol dependence. weak NMDA-receptor antagonist and a GABAA-receptor activator has many molecular effects including actions on GABA, glutamate, serotonergic, noradrenergic, and dopaminergic receptors In chronic alcohol abuse, one of the main mechanisms of tolerance is attributed to GABAA receptors becoming downregulated (i.e. becoming generally less sensitive to the inhibitory effect of the GABA system). When alcohol is no longer consumed, these down-regulated GABAA receptor complexes are so insensitive to GABA that the typical amount of GABA produced has little effect; compounded with the fact that GABA normally inhibits action potential formation, there are not as many receptors for GABA to bind to — meaning that sympathetic activation is unopposed, leading to sympathetic over-stimulation. Acamprosate's mechanism of action is supposed to be, at least partially, due to an enhancement effect on GABA receptors. It has been purported to open the chloride ion channel in a novel way as it does not require GABA as a cofactor, making it less liable for dependence than benzodiazepines. A
- Bicuculline is a convulsant alkaloid. acts as a competitive antagonist at GABAA receptors in that it competitively inhibits GABA binding to these receptors Blocks fast inhibitory synaptic potential Gabazine, a synthetic GABA analogue, is similar. These compounds are useful experimental tools but have no therapeutic uses.
- The best-known compound is Flumazenil is a synthetic BZD derivative (imidazobenzodiazepine) (Table 17–1) that behaves as a specific antagonist @ BZD-binding site (modulatory site) of GABA A receptor. it competitively antagonizes the binding and allosteric effects of benzodiazepines and other ligands (Non-BZD hypnotics) Also antagonizes inverse agonist BZDs. But does not antagonize the actions of barbiturates, meprobamate & ethanol Flumazenil can be used to reverse the effect of benzodiazepine overdosage
- The term inverse agonist (Ch. 2) is applied to drugs that bind to benzodiazepine receptors and exert the opposite effect to that of conventional benzodiazepines, producing signs of increased anxiety and convulsions. βCCE, diazepam-binding inhibitor (see above) and some benzodiazepine analogues show inverse agonist activity. It is possible (see Fig. 43.4) to explain these complexities in terms of the two-state model discussed in Chapter 2, by postulating that the benzodiazepine receptor exists in two distinct conformations, only one of which (A) can bind GABA molecules and open the chloride channel. The other conformation (B) cannot bind GABA.
- Normally with no benzodiazepine receptor ligand present, there is an equilibrium between these two conformations; Benzodiazepine agonists (e.g. diazepam) are postulated to bind preferentially to conformation A, thus shifting the equilibrium in favour of A and enhancing GABA sensitivity. Inverse agonists bind selectively to B and have the opposite effect. Competitive antagonists would bind equally to A and B, and consequently would not disturb the conformational equilibrium but antagonise the effect of both agonists and inverse agonists
- Picrotoxin a plant product is a convulsant that acts by blocking the chloride channel associated with the GABAA receptor, thus blocking the postsynaptic inhibitory effect of GABA. It has no therapeutic uses. Experimental convulsants like pentylenetetrazol and the cage convulsant t-butyl bicyclophosphorothionate (TBPS) act in a manner similar to picrotoxin, preventing Cl− channel permeability. The antibiotic penicillin is a channel blocker with a net negative charge. It blocks the channel by interacting with the positively charged amino acid residues within the channel pore, consequently occluding Cl− passage through the channel
- Benzodiazepines are generally not considered to be analgesic agents. Can be used as adjuvants along with other analgesics Recently, a GABAergic hypothesis of depression was proposed which posits a central role of the GABA system in the pathophysiology of depression62. Moreover, clinical studies have revealed that the benzodiazepines alprazolam and adinazolam elicit antidepressant responses similar to widely prescribed antidepressants in patients with major depressive disorder A recent study examined a role for tonic inhibition mediated by extrasynaptic GABAA receptors in stroke - can improve post-stroke recovery, the fact that in preclinical studies Inverse agonists Beta carbolines – can be used to treat depression Several studies in animals and humans have suggested that classical benzodiazepines can impair learning and memory69, 70, 71. This raises the question whether negative allosteric modulators (inverse agonists) at the benzodiazepine site of GABAA receptors, i.e. compounds which inhibit GABA-induced chloride influx, might have cognition-enhancing actions.
- GABAB receptors are not modulated by benzodiazepines, barbiturates, or steroids, and are not sensitive to bicuculline [218,225]. Characteristic agonists of GABAB receptors are baclofen, a lipophilic derivative of GABA, and 3-aminopropylphosponous acid (3-APPA; CGP27492), while saclofen, phaclofen and 2-hydroxysaclofen act as antagonists of GABAB receptors [12]. Competitive antagonists for the GABAB receptor include a number of experimental compounds (e.g. 2-hydroxysaclofen and more potent compounds with improved brain penetration, such as CGP 35348). Lesogaberan (AZD-3355) was[1] an experimental drug candidate developed by AstraZeneca for the treatment of gastroesophageal reflux disease (GERD).[2] As a GABAB receptor agonist,[3] it has the same mechanism of action as baclofen, Phenibut is a central depressant and close structural analogue of GABA, as well as of baclofen (β-(4-chlorophenyl)-GABA), pregabalin Phenibut is believed to act as a selective GABAB receptor agonist The structure of isovaline is similar to the amino acids GABA and glycine. Isovaline acts as an analgesic in mice [3][4]by activating peripheral GABAB receptors. SKF-97,541 is a compound used in scientific research which acts primarily as a selective GABAB receptor agonist.[1] It has sedative effects in animal studies and is widely used in research into potential treatment of various types of drug addiction. BHFF is a compound used in scientific research which acts as a positive allosteric modulator at the GABAB receptor. It has anxiolytic effects in animal studies, Fasoracetam In studies in rats, it blocked memory disruptions caused by baclofen, a GABAB agonist BSPP is a compound used in scientific research which acts as a positive allosteric modulator at the GABAB receptor Homotaurine is a precursor to acamprosate.
- Baclofen was introduced to the market in 1972 and is used to treat spasticity and skeletal muscle rigidity in patients with spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, and cerebral palsy. However, although GABAB agonists showed promising therapeutic effects in a whole range of other indications, they exhibit numerous side effects, including sedation, tolerance, and muscle relaxation Baclofen is a GABA analogue which acts as a selective agonist of GABAB receptors, and is used as a muscle relaxant. However, it can aggravate absence seizures, and so is not used in epilepsy.
- Tests in animals have shown that these compounds produce only slight effects on CNS function (in contrast to the powerful convulsant effects of GABAA antagonists). The main effect observed, paradoxically, was an antiepileptic action, specifically in an animal model of absence seizures (see Ch. 44), together with enhanced cognitive performance. Whether such compounds will prove to have therapeutic uses remains to be seen.
- Finally, the insensitivity to the GABAA receptor antagonist bicuculline, its resistance to the GABAB-receptor agonist baclofen [32, 35, 44, 45], and the lack of response to the GABAA-receptor modulators, such as benzodiazepines [32, 46], barbiturates, and neurosteroids [32, 47] set apart this class of receptor. The major indications for drugs acting on GABA(C) receptors are in the treatment of visual, sleep and cognitive disorders Four agents have been of great use for the study of GABAρ receptors due to their high selectivity. Cis-4-aminocrotonic acid (CACA) and cis-2-aminomethyl cyclopropanocarboxylic acid (CAMP) are the most selective agonists for GABAρ receptors [32], whereas the 1, 2, 5, 6-tetrahydropyridine-4 methylphosphinic acid (TPMPA) and 3-aminocyclopentyl methylphosphinic acid [(±)-cis-3-ACPMPA] are selective antagonists [33, 34]. Other antagonists reported to be highly specific for GABAρ1 are guanidine-acetic acid, amino-cyclopent-1-enyl phosphinic acid, and 3-aminocyclobutane phosphinic acid [35, 33, 5], whereras cyclothiazide blocks GABAρ2 [36]. Cis-and trans-(3-aminocyclopentanyl) butylphosphinic acid are a new generation of conformationally restricted analogues that competitively block GABAρ receptors and prevent the development of experimental myopia The most promising leads are THIP, a GABA(C) receptor antagonist in addition to its well known activity as a GABA(A) receptor partial agonist, which is being evaluated for sleep therapy, and CGP36742, an orally active GABA(B) and GABA(C) receptor antagonist, which enhances cognition. Analogues of THIP and CGP36742, such as aza-THIP, that are selective for GABA(C) receptors are being developed. TPMPA and related compounds such as P4MPA, PPA and SEPI are also important leads for the development of systemically active selective GABA(C) receptor antagonists.