GABAA receptor

Structure of the nicotinic acetylcholine receptor (nAchR: PDB: 2BG9​) which is very similar to the GABA_A receptor.^[1][2][3]Top: side view of the nAchR embedded in a cell membrane. Bottom: view of the receptor from the extracellular face of the membrane. The subunits are labeled according to the GABA_A nomenclature and the approximate locations of the GABA and benzodiazepine (BZ) binding sites are noted (between the α- and β-subunits and between the α- and γ-subunits respectively).

Schematic structure of the GABA_A receptor. Left: GABA_A monomeric subunit embedded in a lipid bilayer (yellow lines connected to blue spheres). The four transmembrane α-helices (1–4) are depicted as cylinders. The disulfide bond in the N-terminal extracellular domain which is characteristic of the family of cys-loop receptors (which includes the GABA_A receptor) is depicted as a yellow line. Right: Five subunits symmetrically arranged about the central chloride anion conduction pore. The extracellular loops are not depicted for the sake of clarity.

The GABA_A receptor (GABA_AR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABA_A receptor selectively conducts Cl⁻ through its pore. Cl- will flow out of the cell if the internal voltage is less than resting potential and Cl- will flow in if it is more than resting potential (i.e. -75 mV)^[4]. This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring. The reversal potential of the GABA_A-mediated inhibitory postsynaptic potential (IPSP) in normal solution is −70 mV, contrasting the GABA_B IPSP (-100 mV).

The active site of the GABA_A receptor is the binding site for GABA and several drugs such as muscimol, gaboxadol, and bicuculline.^[5] The protein also contains a number of different allosteric binding sites which modulate the activity of the receptor indirectly. These allosteric sites are the targets of various other drugs, including the benzodiazepines, nonbenzodiazepines, neuroactive steroids, barbiturates, alcohol (ethanol),^[6]inhaled anaesthetics, and picrotoxin, among others.^[7]

GABA_A receptors occur in all organisms that have a nervous system. To a limited extent the receptors can be found in non-neuronal tissues. Due to their wide distribution within the nervous system of mammals they play a role in virtually all brain functions.

Contents

• 
  1 Target for benzodiazepines
  


• 
  2 Structure and function
  
  
  
  • 
    2.1 Subunits
    
  
  
  • 
    2.2 Distribution
    
  
  
  
  


• 
  3 Ligands
  
  
  
  • 
    3.1 Types
    
  
  
  • 
    3.2 Examples
    
  
  
  • 
    3.3 Effects
    
  
  
  • 
    3.4 Novel drugs
    
  
  
  
  


• 
  4 See also
  


• 
  5 References
  


• 
  6 Further reading
  


• 
  7 External links
  

Target for benzodiazepines

The ionotropic GABA_A receptor protein complex is also the molecular target of the benzodiazepine class of tranquilizer drugs. Benzodiazepines do not bind to the same receptor site on the protein complex as the endogenous ligand GABA (whose binding site is located between α- and β-subunits), but bind to distinct benzodiazepine binding sites situated at the interface between the α- and γ-subunits of α- and γ-subunit containing GABA_A receptors.^[8][9] While the majority of GABA_A receptors (those containing α₁-, α₂-, α₃-, or α₅-subunits) are benzodiazepine sensitive, there exists a minority of GABA_A receptors (α₄- or α₆-subunit containing) which are insensitive to classical 1,4-benzodiazepines,^[10] but instead are sensitive to other classes of GABAergic drugs such as neurosteroids and alcohol. In addition peripheral benzodiazepine receptors exist which are not associated with GABA_A receptors. As a result, the IUPHAR has recommended that the terms "BZ receptor", "GABA/BZ receptor" and "omega receptor" no longer be used and that the term "benzodiazepine receptor" be replaced with "benzodiazepine site".^[11]

In order for GABA_A receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, between which the benzodiazepine binds. Once bound, the benzodiazepine locks the GABA_A receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABA_A receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarising the membrane. This potentiates the inhibitory effect of the available GABA leading to sedative and anxiolytic effects.^{[citation needed]}

Different benzodiazepines have different affinities for GABA_A receptors made up of different collection of subunits, and this means that their pharmacological profile varies with subtype selectivity. For instance, benzodiazepine receptor ligands with high activity at the α₁ and/or α₅ tend to be more associated with sedation, ataxia and amnesia, whereas those with higher activity at GABA_A receptors containing α₂ and/or α₃ subunits generally have greater anxiolytic activity.^[12]Anticonvulsant effects can be produced by agonists acting at any of the GABA_A subtypes, but current research in this area is focused mainly on producing α₂-selective agonists as anticonvulsants which lack the side effects of older drugs such as sedation and amnesia.

The binding site for benzodiazepines is distinct from the binding site for barbiturates and GABA on the GABA_A receptor, and also produces different effects on binding,^[13] with the benzodiazepines increasing the frequency of the chloride channel opening, while barbiturates increase the duration of chloride channel opening when GABA is bound.^[14] Since these are separate modulatory effects, they can both take place at the same time, and so the combination of benzodiazepines with barbiturates is strongly synergistic, and can be dangerous if dosage is not strictly controlled.

Also note that some GABA_A agonists such as muscimol and gaboxadol do bind to the same site on the GABA_A receptor complex as GABA itself, and consequently produce effects which are similar but not identical to those of positive allosteric modulators like benzodiazepines.^{[citation needed]}

Structure and function

Schematic diagram of a GABA_A receptor protein ((α1)₂(β2)₂(γ2)) which illustrates the five combined subunits that form the protein, the chloride (Cl⁻) ion channel pore, the two GABA active binding sites at the α1 and β2 interfaces, and the benzodiazepine (BDZ) allosteric binding site^[1]

Structural understanding of the GABA_A receptor was initially based on homology models, obtained using crystal structures of homologous proteins like Acetylcholine binding protein (AChBP) and nicotinic acetylcholine (nACh) receptors as templates.^[15][16] The much sought structure of a GABA_A receptor was finally resolved, with the disclosure of the crystal structure of human β3 homopentameric GABA_A receptor.^[17]
Whilst this was a major development, the majority of GABAA receptors are heteromeric and the structure did not provide any details of the benzodiazepine binding site. This was finally elucidated in 2018 by the publication of a high resolution cryo-EM structure of a human α1β2γ2 receptor bound with GABA and the neutral benzodiazepine flumazenil.^[18]

GABA_A receptors are pentameric transmembrane receptors which consist of five subunits arranged around a central pore. Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly. The receptor sits in the membrane of its neuron, usually localized at a synapse, postsynaptically. However, some isoforms may be found extrasynaptically.^[19] The ligand GABA is the 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. Because the reversal potential for chloride in most neurons is close to or more negative than the resting membrane potential, activation of GABA_A receptors tends to stabilize or hyperpolarise the resting potential, and can make it more difficult for excitatory neurotransmitters to depolarize the neuron and generate an action potential. The net effect is typically inhibitory, reducing the activity of the neuron. However, depolarizing responses have been found to occur in response to GABA in immature neurons due to a modified Cl- gradient.^[20] These depolarization events have shown to be key in neuronal development.^[21] In the mature neuron, the GABA_A channel opens quickly and thus contributes to the early part of the inhibitory post-synaptic potential (IPSP).^[22][23]
The endogenous ligand that binds to the benzodiazepine site is inosine.^{[24][citation needed]}

Subunits

GABA_A receptors are members of the large pentameric ligand gated ion channel (previously referred to as "Cys-loop" receptors) super-family of evolutionarily related and structurally similar ligand-gated ion channels that also includes nicotinic acetylcholine receptors, glycine receptors, and the 5HT₃ receptor. There are numerous subunit isoforms for the GABA_A receptor, which determine the receptor's agonist affinity, chance of opening, conductance, and other properties.^[25]

In humans, the units are as follows:^[26]

• six types of α subunits (GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6)


• three βs (GABRB1, GABRB2, GABRB3)


• three γs (GABRG1, GABRG2, GABRG3)


• as well as a δ (GABRD), an ε (GABRE), a π (GABRP), and a θ (GABRQ)

There are three ρ units (GABRR1, GABRR2, GABRR3); however, these do not coassemble with the classical GABA_A units listed above,^[27] but rather homooligomerize to form GABA_A-ρ receptors (formerly classified as GABA_C receptors but now this nomenclature has been deprecated^[28] ).

Distribution

GABA_A receptors are responsible for most of the physiological activities of GABA in the central nervous system, and the receptor subtypes vary significantly. Subunit composition can vary widely between regions and subtypes may be associated with specific functions. The minimal requirement to produce a GABA-gated ion channel is the inclusion of an α and a β subunit.^[29] The most common GABA_A receptor is a pentamer comprising two α's, two β's, and a γ (α₁β₂γ₂).^[26] In neurons themselves, the type of GABA_A receptor subunits and their densities can vary between cell bodies and dendrites.^[30] GABA_A receptors can also be found in other tissues, including leydig cells, placenta, immune cells, liver, bone growth plates and several other endocrine tissues. Subunit expression varies between 'normal' tissue and malignancies, as GABA_A receptors can influence cell proliferation.^[31]

Distribution of Receptor Types^[32]

Isoform	Synaptic/Extrasynaptic	Anatomical location
α1β3γ2S	Both	Widespread
α2β3γ2S	Both	Widespread
α3β3γ2S	Both	Reticular thalamic nucleus
α4β3γ2S	Both	Thalamic relay cells
α5β3γ2S	Both	Hippocampal pyramidal cells
α6β3γ2S	Both	Cerebellar granule cells
α1β2γ2S	Both	Widespread, most abundant
α4β3δ	Extrasynaptic	Thalamic relay cells
α6β3δ	Extrasynaptic	Cerebellar granule cells
α1β2	Extrasynaptic	Widespread
α1β3	Extrasynaptic	Thalamus, hypothalamus
α1β2δ	Extrasynaptic	Hippocampus
α4β2δ	Extrasynaptic	Hippocampus
α3β3θ	Extrasynaptic	Hypothalamus
α3β3ε	Extrasynaptic	Hypothalamus

Ligands

GABA_A receptor and where various ligands bind.

A number of ligands have been found to bind to various sites on the GABA_A receptor complex and modulate it besides GABA itself.^[which?] A ligand can possess one or more properties of the following types. Unfortunately the literature often does not distinguish these types properly.

Types

• 
  Orthosteric agonists and antagonists: bind to the main receptor site (the site where GABA normally binds, also referred to as the "active" or "orthosteric" site). Agonists activate the receptor, resulting in increased Cl⁻ conductance. Antagonists, though they have no effect on their own, compete with GABA for binding and thereby inhibit its action, resulting in decreased Cl⁻ conductance.


• 
  First order allosteric modulators: bind to allosteric sites on the receptor complex and affect it either in a positive (PAM), negative (NAM) or neutral/silent (SAM) manner, causing increased or decreased efficiency of the main site and therefore an indirect increase or decrease in Cl⁻ conductance. SAMs do not affect the conductance, but occupy the binding site.


• 
  Second order modulators: bind to an allosteric site on the receptor complex and modulate the effect of first order modulators.


• 
  Open channel blockers: prolong ligand-receptor occupancy, activation kinetics and Cl ion flux in a subunit configuration-dependent and sensitization-state dependent manner.^[33]
  


• 
  Non-competitive channel blockers: bind to or near the central pore of the receptor complex and directly block Cl⁻ conductance through the ion channel.

Examples

• Orthosteric agonists: GABA, gaboxadol, isoguvacine, muscimol, progabide, piperidine-4-sulfonic acid (partial agonist).


• Orthosteric antagonists: bicuculline, gabazine.


• Positive allosteric modulators: barbiturates, benzodiazepines, certain carbamates (ex. carisoprodol, meprobamate, lorbamate), thienodiazepines, alcohol (ethanol), etomidate, glutethimide, kavalactones,^[34]meprobamate, quinazolinones (ex. methaqualone, etaqualone, diproqualone), neuroactive steroids,^[35]niacin/niacinamide,^[36]nonbenzodiazepines (ex. zolpidem, eszopiclone), propofol, stiripentol,^[37]theanine,^{[citation needed]}valerenic acid, volatile/inhaled anesthetics, lanthanum,^[38] and riluzole.^[39]
  


• Negative allosteric modulators: flumazenil, Ro15-4513, sarmazenil, amentoflavone, and zinc.^[40]
  


• Second-order modulators: (−)‐epigallocatechin‐3‐gallate^{[citation needed]}.


• Non-competitive channel blockers: cicutoxin, oenanthotoxin, pentylenetetrazol, picrotoxin^{[citation needed]}, thujone, and lindane.

Effects

Ligands which contribute to receptor activation typically have anxiolytic, anticonvulsant, amnesic, sedative, hypnotic, euphoriant, and muscle relaxant properties. Some such as muscimol and the z-drugs may also be hallucinogenic.^{[citation needed]} Ligands which decrease receptor activation usually have opposite effects, including anxiogenesis and convulsion.^{[citation needed]} Some of the subtype-selective negative allosteric modulators such as α₅IA are being investigated for their nootropic effects, as well as treatments for the unwanted side effects of other GABAergic drugs.^[41]

Novel drugs

A useful property of the many benzodiazepine site allosteric modulators is that they may display selective binding to particular subsets of receptors comprising specific subunits. This allows one to determine which GABA_A receptor subunit combinations are prevalent in particular brain areas and provides a clue as to which subunit combinations may be responsible for behavioral effects of drugs acting at GABA_A receptors. These selective ligands may have pharmacological advantages in that they may allow dissociation of desired therapeutic effects from undesirable side effects.^[42] Few subtype selective ligands have gone into clinical use as yet, with the exception of zolpidem which is reasonably selective for α₁, but several more selective compounds are in development such as the α₃-selective drug adipiplon. There are many examples of subtype-selective compounds which are widely used in scientific research, including:

• 
  CL-218,872 (highly α₁-selective agonist)


• 
  bretazenil (subtype-selective partial agonist)


• 
  imidazenil and L-838,417 (both partial agonists at some subtypes, but weak antagonists at others)


• 
  QH-ii-066 (full agonist highly selective for α₅ subtype)


• 
  α₅IA (selective inverse agonist for α₅ subtype)


• 
  SL-651,498 (full agonist at α₂ and α₃ subtypes, and as a partial agonist at α₁ and α₅
  


• 3-acyl-4-quinolones: selective for α₁ over α₃^[43]
  

See also

• 4-Iodopropofol


• GABA receptor


• GABA_B receptor


• GABA_A-ρ receptor


• Gephyrin


• Glycine receptor


• GABA_A receptor positive allosteric modulators


• GABA_A receptor negative allosteric modulators

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Further reading

.mw-parser-output .refbegin{font-size:90%;margin-bottom:0.5em}.mw-parser-output .refbegin-hanging-indents>ul{list-style-type:none;margin-left:0}.mw-parser-output .refbegin-hanging-indents>ul>li,.mw-parser-output .refbegin-hanging-indents>dl>dd{margin-left:0;padding-left:3.2em;text-indent:-3.2em;list-style:none}.mw-parser-output .refbegin-100{font-size:100%}

• 
  Olsen RW, DeLorey TM (1999). "Chapter 16: GABA and Glycine". In Siegel GJ, Agranoff BW, Fisher SK, Albers RW, Uhler MD. Basic neurochemistry: molecular, cellular, and medical aspects (Sixth ed.). Philadelphia: Lippincott-Raven. ISBN 978-0-397-51820-3.
  


• 
  Olsen RW, Betz H (2005). "Chapter 16: GABA and Glycine". In Siegel GJ, Albers RW, Brady S, Price DD. Basic Neurochemistry: Molecular, Cellular and Medical Aspects (Seventh ed.). Boston: Academic Press. pp. 291–302. ISBN 978-0-12-088397-4.
  


• 
  Uusi-Oukari M, Korpi ER (March 2010). "Regulation of GABA(A) receptor subunit expression by pharmacological agents". Pharmacological Reviews. 62 (1): 97–135. doi:10.1124/pr.109.002063. PMID 20123953.
  


• 
  Rudolph U (2015). Diversity and Functions of GABA Receptors: A Tribute to Hanns Möhler (First ed.). Academic Press, Elsevier. ISBN 978-0-12-802660-1.
  

External links

• 
  Receptors,+GABA-A at the US National Library of Medicine Medical Subject Headings (MeSH)

v t e Ion channel, cell surface receptor: ligand-gated ion channels
Cys-loop receptors	5-HT/serotonin 5-HT3 A B C D E GABA GABAA α1 α2 α3 α4 α5 α6 β1 β2 β3 γ1 γ2 γ3 δ ε π θ GABAA-ρ ρ1 ρ2 ρ3 Glycine α1 α2 α3 α4 β Nicotinic acetylcholine monomers: α1 α2 α3 α4 α5 α6 α7 α9 α10 β1 β2 β3 β4 δ ε pentamers: (α3)2(β4)3 (α4)2(β2)3 (α7)5 (α1)2(β4)3 - Ganglion type (α1)2β1δε - Muscle type Zinc Zinc-activated
Ionotropic glutamates	Ligand-gated only AMPA (1 2 3 4) Kainate 1 2 3 4 5 Voltage- and ligand-gated NMDA 1 2A 2B 2C 2D 3A 3B L1A L1B ‘Orphan’ GluD δ1 δ2
ATP-gated channels	Purinergic receptors P2X 1 2 3 4 5 6 7

v t e GABA receptor modulators
Ionotropic	GABAA Agonists: (+)-Catechin Bamaluzole Barbiturates (e.g., phenobarbital) BL-1020 DAVA Dihydromuscimol GABA Gabamide GABOB Gaboxadol (THIP) Homotaurine (tramiprosate, 3-APS) Ibotenic acid iso-THAZ iso-THIP Isoguvacine Isomuscimol Isonipecotic acid Kojic amine Lignans (e.g., honokiol) Methylglyoxal Monastrol Muscimol Nefiracetam Neuroactive steroids (e.g., allopregnanolone) Org 20599 PF-6372865 Phenibut Picamilon P4S Progabide Propofol Quisqualamine SL-75102 TACA TAMP Terpenoids (e.g., borneol) Thiomuscimol Tolgabide ZAPA Positive modulators (abridged; see here for a full list): α-EMTBL Alcohols (e.g., ethanol) 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 Nicotinamide (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) Antagonists: Bicuculline Coriamyrtin Dihydrosecurinine Gabazine (SR-95531) Hydrastine Hyenachin (mellitoxin) PHP-501 Pitrazepin Securinine Sinomenine SR-42641 SR-95103 Thiocolchicoside Tutin Negative modulators: 1,3M1B 3M2B 11-Ketoprogesterone 17-Phenylandrostenol 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 Iomazenil (123I) IPTBO Isopregnanolone (sepranolone) L-655,708 Laudanosine Leptazol 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 and dihydropicrotoxinin) 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 Agonists: BL-1020 CACA CAMP Homohypotaurine GABA GABOB Ibotenic acid Isoguvacine Muscimol N4-Chloroacetylcytosine arabinoside Picamilon Progabide TACA TAMP Thiomuscimol Tolgabide Positive modulators: Allopregnanolone Alphaxolone ATHDOC Lanthanides Antagonists: (S)-2-MeGABA (S)-4-ACPBPA (S)-4-ACPCA 2-MeTACA 3-APMPA 4-ACPAM 4-GBA cis-3-ACPBPA CGP-36742 (SGS-742) DAVA Gabazine (SR-95531) Gaboxadol (THIP) I4AA Isonipecotic acid Loreclezole P4MPA P4S SKF-97541 SR-95318 SR-95813 TPMPA trans-3-ACPBPA ZAPA Negative modulators: 5α-Dihydroprogesterone Bilobalide Loreclezole Picrotoxin (picrotin, picrotoxinin) Pregnanolone ROD-188 THDOC Zinc
Metabotropic	GABAB Agonists: 1,4-Butanediol 4-Fluorophenibut Aceburic acid Arbaclofen Arbaclofen placarbil Baclofen BL-1020 GABA Gabamide GABOB GBL GHB GHBAL GHV GVL Isovaline Lesogaberan Phenibut Picamilon Progabide Sodium oxybate SKF-97,541 SL 75102 Tolgabide Tolibut Positive modulators: ADX-71441 BHF-177 BHFF BSPP CGP-7930 CGP-13501 GS-39783 rac-BHFF KK-92A Antagonists: 2-Hydroxysaclofen CGP-35348 CGP-46381 CGP-52432 CGP-54626 CGP-55845 CGP-64213 DAVA Homotaurine (tramiprosate, 3-APS) Phaclofen Saclofen SCH-50911 SKF-97541 Negative modulators: Compound 14
See also Receptor/signaling modulators GABAA receptor positive modulators GABA metabolism/transport modulators

v t e GABAA receptor positive modulators
Alcohols	Brometone Butanol Chloralodol Chlorobutanol (cloretone) Ethanol (alcohol) (alcoholic drink) Ethchlorvynol Isobutanol Isopropanol Menthol Methanol Methylpentynol Pentanol Petrichloral Propanol tert-Butanol (2M2P) tert-Pentanol (2M2B) Tribromoethanol Trichloroethanol Triclofos Trifluoroethanol
Barbiturates	(-)-DMBB Allobarbital Alphenal Amobarbital Aprobarbital Barbexaclone Barbital Benzobarbital Benzylbutylbarbiturate Brallobarbital Brophebarbital Butabarbital/Secbutabarbital Butalbital Buthalital Butobarbital Butallylonal Carbubarb Crotylbarbital Cyclobarbital Cyclopentobarbital Difebarbamate Enallylpropymal Ethallobarbital Eterobarb Febarbamate Heptabarb Heptobarbital Hexethal Hexobarbital Metharbital Methitural Methohexital Methylphenobarbital Narcobarbital Nealbarbital Pentobarbital Phenallymal Phenobarbital Phetharbital Primidone Probarbital Propallylonal Propylbarbital Proxibarbital Reposal Secobarbital Sigmodal Spirobarbital Talbutal Tetrabamate Tetrabarbital Thialbarbital Thiamylal Thiobarbital Thiobutabarbital Thiopental Thiotetrabarbital Valofane Vinbarbital Vinylbital
Benzodiazepines	2-Oxoquazepam 3-Hydroxyphenazepam Adinazolam Alprazolam Arfendazam Avizafone Bentazepam Bretazenil Bromazepam Brotizolam Camazepam Carburazepam Chlordiazepoxide Ciclotizolam Cinazepam Cinolazepam Clazolam Climazolam Clobazam Clonazepam Clonazolam Cloniprazepam Clorazepate Clotiazepam Cloxazolam CP-1414S Cyprazepam Delorazepam Demoxepam Diazepam Diclazepam Doxefazepam Elfazepam Estazolam Ethyl carfluzepate Ethyl dirazepate Ethyl loflazepate Etizolam EVT-201 FG-8205 Fletazepam Flubromazepam Flubromazolam Fludiazepam Flunitrazepam Flunitrazolam Flurazepam Flutazolam Flutemazepam Flutoprazepam Fosazepam Gidazepam Halazepam Haloxazolam Iclazepam Imidazenil Irazepine Ketazolam Lofendazam Lopirazepam Loprazolam Lorazepam Lormetazepam Meclonazepam Medazepam Menitrazepam Metaclazepam Mexazolam Midazolam Motrazepam N-Desalkylflurazepam Nifoxipam Nimetazepam Nitrazepam Nitrazepate Nitrazolam Nordazepam Nortetrazepam Oxazepam Oxazolam Phenazepam Pinazepam Pivoxazepam Prazepam Premazepam Proflazepam Pyrazolam QH-II-66 Quazepam Reclazepam Remimazolam Rilmazafone Ripazepam Ro48-6791 Ro48-8684 SH-053-R-CH3-2′F Sulazepam Temazepam Tetrazepam Tolufazepam Triazolam Triflubazam Triflunordazepam (Ro5-2904) Tuclazepam Uldazepam Zapizolam Zolazepam Zomebazam
Carbamates	Carisbamate Carisoprodol Clocental Cyclarbamate Difebarbamate Emylcamate Ethinamate Febarbamate Felbamate Hexapropymate Lorbamate Mebutamate Meprobamate Nisobamate Pentabamate Phenprobamate Procymate Styramate Tetrabamate Tybamate
Flavonoids	6-Methylapigenin Ampelopsin (dihydromyricetin) Apigenin Baicalein Baicalin Catechin EGC EGCG Hispidulin Linarin Luteolin Rc-OMe Skullcap constituents (e.g., baicalin) Wogonin
Imidazoles	Etomidate Metomidate Propoxate
Kava constituents	10-Methoxyyangonin 11-Methoxyyangonin 11-Hydroxyyangonin Desmethoxyyangonin 11-Methoxy-12-hydroxydehydrokavain 7,8-Dihydroyangonin Kavain 5-Hydroxykavain 5,6-Dihydroyangonin 7,8-Dihydrokavain 5,6,7,8-Tetrahydroyangonin 5,6-Dehydromethysticin Methysticin 7,8-Dihydromethysticin Yangonin
Monoureides	Acecarbromal Apronal (apronalide) Bromisoval Carbromal Capuride Ectylurea
Neuroactive steroids	Acebrochol Allopregnanolone (brexanolone) Alfadolone Alfaxalone 3α-Androstanediol Androstenol Androsterone Certain anabolic-androgenic steroids Cholesterol DHDOC 3α-DHP 5α-DHP 5β-DHP DHT Etiocholanolone Ganaxolone Hydroxydione Minaxolone ORG-20599 ORG-21465 P1-185 Pregnanolone (eltanolone) Progesterone Renanolone SAGE-105 SAGE-324 SAGE-516 SAGE-689 SAGE-872 Testosterone THDOC Zuranolone
Nonbenzodiazepines	β-Carbolines: Abecarnil Gedocarnil Harmane SL-651,498 ZK-93423 Cyclopyrrolones: Eszopiclone Pagoclone Pazinaclone Suproclone Suriclone Zopiclone Imidazopyridines: Alpidem DS-1 Necopidem Saripidem Zolpidem Pyrazolopyrimidines: Divaplon Fasiplon Indiplon Lorediplon Ocinaplon Panadiplon Taniplon Zaleplon Others: Adipiplon CGS-8216 CGS-9896 CGS-13767 CGS-20625 CL-218,872 CP-615,003 CTP-354 ELB-139 GBLD-345 Imepitoin JM-1232 L-838,417 Lirequinil (Ro41-3696) NS-2664 NS-2710 NS-11394 Pipequaline ROD-188 RWJ-51204 SB-205,384 SX-3228 TGSC01AA TP-003 TPA-023 TP-13 U-89843A U-90042 Viqualine Y-23684
Phenols	Fospropofol Propofol Thymol
Piperidinediones	Glutethimide Methyprylon Piperidione Pyrithyldione
Pyrazolopyridines	Cartazolate Etazolate ICI-190,622 Tracazolate
Quinazolinones	Afloqualone Cloroqualone Diproqualone Etaqualone Mebroqualone Mecloqualone Methaqualone Methylmethaqualone Nitromethaqualone SL-164
Volatiles/gases	Acetone Acetophenone Acetylglycinamide chloral hydrate Aliflurane Benzene Butane Butylene Centalun Chloral Chloral betaine Chloral hydrate Chloroform Cryofluorane Desflurane Dichloralphenazone Dichloromethane Diethyl ether Enflurane Ethyl chloride Ethylene Fluroxene Gasoline Halopropane Halothane Isoflurane Kerosine Methoxyflurane Methoxypropane Nitric oxide Nitrogen Nitrous oxide Norflurane Paraldehyde Propane Propylene Roflurane Sevoflurane Synthane Teflurane Toluene Trichloroethane (methyl chloroform) Trichloroethylene Vinyl ether
Others/unsorted	3-Hydroxybutanal α-EMTBL AA-29504 Avermectins (e.g., ivermectin) Bromide compounds (e.g., lithium bromide, potassium bromide, sodium bromide) Carbamazepine Chloralose Chlormezanone Clomethiazole DEABL Dihydroergolines (e.g., dihydroergocryptine, dihydroergosine, dihydroergotamine, ergoloid (dihydroergotoxine)) DS2 Efavirenz Etazepine Etifoxine Fenamates (e.g., flufenamic acid, mefenamic acid, niflumic acid, tolfenamic acid) Fluoxetine Flupirtine Hopantenic acid Lanthanum Lavender oil Lignans (e.g., 4-O-methylhonokiol, honokiol, magnolol, obovatol) Loreclezole Menthyl isovalerate (validolum) Monastrol Niacin Nicotinamide (niacinamide) Org 25,435 Phenytoin Propanidid Retigabine (ezogabine) Safranal Seproxetine Stiripentol Sulfonylalkanes (e.g., sulfonmethane (sulfonal), tetronal, trional) Terpenoids (e.g., borneol) Topiramate Valerian constituents (e.g., isovaleric acid, isovaleramide, valerenic acid, valerenol) Unsorted benzodiazepine site positive modulators: α-Pinene MRK-409 (MK-0343) TCS-1105 TCS-1205
See also: Receptor/signaling modulators • GABA receptor modulators • GABA metabolism/transport modulators

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