Category of drug
γ-Aminobutyric acid (GABA), a GABA receptor agonist.AGABA receptor agonist is adrug that is anagonist for one or more of theGABA receptors , producing typicallysedative effects, and may also cause other effects such asanxiolytic ,anticonvulsant , andmuscle relaxant effects.[ 1]
There are three receptors of GABA. TheGABAA andGABAA -ρ receptors areion channels that are permeable tochloride ions which reducesneuronal excitability . TheGABAB receptor belongs to the class ofG protein-coupled receptors that inhibitadenylyl cyclase , therefore leading to decreasedcyclic adenosine monophosphate (cAMP). The GABAA receptor mediates sedative andhypnotic effects and as well asanticonvulsant effects. The GABAB receptor mediates similar but differing effects.
Many commonly usedsedative andanxiolytic drugs that affect the GABA receptor complex are not agonists. These drugs act instead aspositive allosteric modulators (PAMs) and while they do bind to the GABA receptors, they bind to an allosteric site on the receptor and cannot induce a response from the neuron without an actual agonist being present. Drugs that fall into this class exert their pharmacodynamic action by increasing the effects that an agonist has whenpotentiation is achieved.
General anesthetics act primarily as PAMs of GABA-A receptor.Positive allosteric modulators work by increasing the frequency with which the chloride channel opens when an agonist binds to its own site on the GABA receptor. The resulting increase in the concentration of Cl− ions in the postsynaptic neuron immediately hyperpolarizes this neuron, making it less excitable and thus inhibiting the possibility of anaction potential . However, some general anesthetics like propofol and high doses of barbiturates may not only be positive allosteric modulators of GABA-A receptors but also direct agonists of these receptors.
Alcohol is an indirectGABA agonist. GABA is the major inhibitoryneurotransmitter in the brain, and GABA-like drugs are used to suppress spasms. Alcohol is believed to mimic GABA's effect in the brain, binding to GABA receptors and inhibiting neuronal signaling.
Positive allosteric modulators [ edit ] Alcohols (e.g.,ethanol ,isopropanol )Avermectins (e.g.,ivermectin )Barbiturates (e.g.,phenobarbital )Benzodiazepines (e.g.,diazepam ,alprazolam )Bromides (e.g.,potassium bromide )Carbamates (e.g.,meprobamate ,carisoprodol )Chloral hydrate ,chloralose ,petrichloral , and other2,2,2-trichloroethanol prodrugs Chlormezanone Clomethiazole Dihydroergolines (e.g.,ergoloid (dihydroergotoxine) )Etazepine Etifoxine 2-Substitutedphenols (e.g.,thymol ,eugenol ) Imidazoles (e.g.,etomidate )Kavalactones (found inkava )Loreclezole Neuroactive steroids (e.g.,allopregnanolone ,ganaxolone )Nonbenzodiazepines (e.g.,zaleplon ,zolpidem ,zopiclone ,eszopiclone )Propofol Piperidinediones (e.g.,glutethimide ,methyprylon )Propanidid Pyrazolopyridines (e.g.,etazolate )Quinazolinones (e.g.,methaqualone )Skullcap constituents (e.g.,Baicalein )Stiripentol Disulfonylalkanes (e.g.,sulfonmethane ,tetronal ,trional ) Valerian constituents (e.g.,valeric acid ,valerenic acid )Volatile organic compounds (e.g.,chloroform ,diethyl ether ,sevoflurane )Positive allosteric modulators [ edit ] Positive allosteric modulators [ edit ] ^ Brohan J, Goudra BG (October 2017). "The Role of GABA Receptor Agonists in Anesthesia and Sedation".CNS Drugs .31 (10):845– 856.doi :10.1007/s40263-017-0463-7 .PMID 29039138 .S2CID 207486777 . ^ Petersen JG, Bergmann R, Møller HA, Jørgensen CG, Nielsen B, Kehler J, Frydenvang K, Kristensen J, Balle T, Jensen AA, Kristiansen U, Frølund B (February 2013). "Synthesis and biological evaluation of 4-(aminomethyl)-1-hydroxypyrazole analogues of muscimol as γ-aminobutyric acid(a) receptor agonists".J Med Chem .56 (3):993– 1006.doi :10.1021/jm301473k .PMID 23294161 . ^ Löscher W, Rogawski MA (December 2012)."How theories evolved concerning the mechanism of action of barbiturates" .Epilepsia .53 (Suppl 8):12– 25.doi :10.1111/epi.12025 PMID 23205959 .S2CID 4675696 . ^a b c d e f Ganellin CR, Triggle DJ, Macdonald F (1996).Dictionary of Pharmacological Agents ISBN 978-0-412-46630-4 ^a b Ruesch D, Neumann E, Wulf H, Forman SA (January 2012)."An allosteric coagonist model for propofol effects on α1β2γ2L γ-aminobutyric acid type A receptors" .Anesthesiology .116 (1):47– 55.doi :10.1097/aln.0b013e31823d0c36 .PMC 3261780 PMID 22104494 . ^ Hales TG, Lambert JJ (November 1991)."The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones" .British Journal of Pharmacology .104 (3):619– 628.doi :10.1111/j.1476-5381.1991.tb12479.x .PMC 1908220 PMID 1665745 .
Ionotropic
GABAA Tooltip γ-Aminobutyric acid A receptor Positive modulators (abridged; seehere for a full list): α-EMTBL Alcohols (e.g.,drinking alcohol ,2M2B )Anabolic steroids Avermectins (e.g.,ivermectin )Barbiturates (e.g.,phenobarbital )Benzodiazepines (e.g.,diazepam )Bromide compounds (e.g.,potassium bromide )Carbamates (e.g.,meprobamate )Carbamazepine Chloralose Chlormezanone Clomethiazole Dihydroergolines (e.g.,ergoloid (dihydroergotoxine) )Etazepine Etifoxine Fenamates (e.g.,mefenamic acid )Flavonoids (e.g.,apigenin ,hispidulin )Fluoxetine Flupirtine Imidazoles (e.g.,etomidate )Kava constituents (e.g.,kavain )Lanthanum Loreclezole Monastrol Neuroactive steroids (e.g.,allopregnanolone ,cholesterol ,THDOC )Niacin Niacinamide Nonbenzodiazepines (e.g.,β-carbolines (e.g.,abecarnil ),cyclopyrrolones (e.g.,zopiclone ),imidazopyridines (e.g.,zolpidem ),pyrazolopyrimidines (e.g.,zaleplon ))Norfluoxetine Petrichloral Phenols (e.g.,propofol )Phenytoin Piperidinediones (e.g.,glutethimide )Propanidid Pyrazolopyridines (e.g.,etazolate )Quinazolinones (e.g.,methaqualone )Retigabine (ezogabine) ROD-188 Skullcap constituents (e.g.,baicalin )Stiripentol Sulfonylalkanes (e.g.,sulfonmethane (sulfonal) )Topiramate Valerian constituents (e.g.,valerenic acid )Volatiles /gases (e.g.,chloral hydrate ,chloroform ,diethyl ether ,paraldehyde ,sevoflurane )Negative modulators: 1,3M1B 3M2B 11-Ketoprogesterone 17-Phenylandrostenol α3IA α5IA (LS-193,268) β-CCB β-CCE β-CCM β-CCP β-EMGBL Anabolic steroids Amiloride Anisatin β-Lactams (e.g.,penicillins ,cephalosporins ,carbapenems )Basmisanil Bemegride Bicyclic phosphates (TBPS ,TBPO ,IPTBO )BIDN Bilobalide Bupropion CHEB Chlorophenylsilatrane Cicutoxin Cloflubicyne Cyclothiazide DHEA DHEA-S Dieldrin (+)-DMBB DMCM DMPC EBOB Etbicyphat FG-7142 (ZK-31906) Fiproles (e.g.,fipronil )Flavonoids (e.g.,amentoflavone ,oroxylin A )Flumazenil Fluoroquinolones (e.g.,ciprofloxacin )Flurothyl Furosemide Golexanolone Iomazenil (123 I) IPTBO Isopregnanolone (sepranolone) L-655,708 Laudanosine Lindane MaxiPost Morphine Morphine-3-glucuronide MRK-016 Naloxone Naltrexone Nicardipine Nonsteroidal antiandrogens (e.g.,apalutamide ,bicalutamide ,enzalutamide ,flutamide ,nilutamide )Oenanthotoxin Pentylenetetrazol (pentetrazol) Phenylsilatrane Picrotoxin (i.e.,picrotin ,picrotoxinin anddihydropicrotoxinin )Pregnenolone sulfate Propybicyphat PWZ-029 Radequinil Ro 15-4513 Ro 19-4603 RO4882224 RO4938581 Sarmazenil SCS Suritozole TB-21007 TBOB TBPS TCS-1105 Terbequinil TETS Thujone U-93631 Zinc ZK-93426 GABAA -ρ Tooltip γ-Aminobutyric acid A-rho receptor
Metabotropic
GABAB Tooltip γ-Aminobutyric acid B receptor
