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The GABAA receptor
GABAA receptor
(GABAAR) 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 GABAA receptor
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 reversal potential of the GABAA-mediated IPSP in normal solution is −70 mV, contrasting the GABAB IPSP. The active site of the GABAA receptor
GABAA receptor
is the binding site for GABA
GABA
and several drugs such as muscimol, gaboxadol, and bicuculline.[4] 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),[5] inhaled anaesthetics, and picrotoxin, among others.[6] GABAA 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 External links

Target for benzodiazepines[edit] The ionotropic GABAA receptor
GABAA 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
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 GABAA receptors.[7][8] While the majority of GABAA receptors (those containing α1-, α2-, α3-, or α5-subunits) are benzodiazepine sensitive, there exists a minority of GABAA receptors (α4- or α6-subunit containing) which are insensitive to classical 1,4-benzodiazepines,[9] 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 GABAA 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".[10] In order for GABAA 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 GABAA receptor
GABAA receptor
into a conformation where the neurotransmitter GABA has much higher affinity for the GABAA 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
GABA
leading to sedative and anxiolytic effects.[citation needed] Different benzodiazepines have different affinities for GABAA 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 GABAA receptors containing α2 and/or α3 subunits generally have greater anxiolytic activity.[11] Anticonvulsant
Anticonvulsant
effects can be produced by agonists acting at any of the GABAA 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
GABA
on the GABAA receptor, and also produces different effects on binding,[12] with the benzodiazepines causing bursts of chloride channel opening to occur more often, while the barbiturates cause the duration of bursts of chloride channel opening to become longer.[13] 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 GABAA agonists such as muscimol and gaboxadol do bind to the same site on the GABAA receptor
GABAA receptor
complex as GABA
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[edit]

Schematic diagram of a GABAA receptor
GABAA 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
GABA
active binding sites at the α1 and β2 interfaces, and the benzodiazepine (BDZ) allosteric binding site[1]

Structural understanding of the GABAA receptor
GABAA 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.[14][15] The much sought structure of GABAA receptor
GABAA receptor
was finally resolved, with the disclosure of the crystal structure of human β3 homopentameric GABAA receptor.[16] GABAA receptor
GABAA receptor
is a pentameric transmembrane receptor that consists 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.[17] The ligand GABA
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 GABAA 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
GABA
in immature neurons due to a modified Cl- gradient.[18] These depolarization events have shown to be key in neuronal development.[19] In the mature neuron, the GABAA channel opens quickly and thus contributes to the early part of the inhibitory post-synaptic potential (IPSP).[20][21] The endogenous ligand that binds to the benzodiazepine site is inosine.[22][citation needed] Subunits[edit] GABAA receptors are members of the large "Cys-loop" 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 GABAA receptor, which determine the receptor's agonist affinity, chance of opening, conductance, and other properties.[23] In humans, the units are as follows:[24]

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 GABAA units listed above,[25] but rather homooligomerize to form GABAA-ρ receptors (formerly classified as GABAC receptors but now this nomenclature has been deprecated[26] ). Distribution[edit] GABAA receptors are responsible for most of the physiological activities of GABA
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.[27] The most common GABAA receptor is a pentamer comprising two α's, two β's, and a γ (α1β2γ2).[24] In neurons themselves, the type of GABAA receptor subunits and their densities can vary between cell bodies and dendrites.[28] Interestingly, GABAA 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 GABAA receptors can influence cell proliferation.[29]

Distribution of Receptor Types[30]

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[edit]

GABAA receptor
GABAA receptor
and where various ligands bind.

A number of ligands have been found to bind to various sites on the GABAA receptor
GABAA receptor
complex and modulate it besides GABA
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[edit]

Orthosteric agonists and antagonists: bind to the main receptor site (the site where GABA
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
GABA
for binding and thereby inhibit its action, resulting in decreased Cl− conductance. Allosteric
Allosteric
agonists: bind to allosteric sites on the receptor and activate the receptor in absence of orthosteric ligands. 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.[31] 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[edit]

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,[32] meprobamate, quinazolinones (ex. methaqualone, etaqualone, diproqualone), neuroactive steroids,[33] niacin/niacinamide,[34] nonbenzodiazepines (ex. zolpidem, eszopiclone), propofol, stiripentol,[35] theanine,[citation needed] valerenic acid, volatile/inhaled anesthetics, lanthanum,[36] and riluzole.[37] Negative allosteric modulators: flumazenil, Ro15-4513, sarmazenil, amentoflavone, and zinc.[38] Second-order modulators: (−)‐epigallocatechin‐3‐gallate. Non-competitive channel blockers: cicutoxin, oenanthotoxin, pentylenetetrazol, picrotoxin, thujone, and lindane.

Effects[edit] 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.[39] Novel drugs[edit] 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 GABAA receptor
GABAA 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 GABAA receptors. These selective ligands may have pharmacological advantages in that they may allow dissociation of desired therapeutic effects from undesirable side effects.[40] 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
CL-218,872
(highly α1-selective agonist) bretazenil (subtype-selective partial agonist) imidazenil and L-838,417
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
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[41]

See also[edit]

4-Iodopropofol GABA
GABA
receptor GABAB receptor GABAA-ρ receptor Gephyrin Glycine receptor GABAA receptor
GABAA receptor
positive allosteric modulators

References[edit]

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External links[edit]

Receptors, GABA-A at the US National Library of Medicine Medical Subject Headings (MeSH) Olsen RW, DeLorey TM (1999). "Chapter 16: GABA
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 0-397-51820-X.  Olsen RW, Betz H (2005). "Chapter 16: GABA
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 0-12-088397-X.  Uusi-Oukari, M; Korpi, ER (2010). "Regulation of GABAA 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
GABA
Receptors: A Tribute to Hanns Möhler (First ed.). Academic Press, Elsevier. ISBN 978-0-12-802660-1. 

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
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
GABA
receptor modulators

Ionotropic

GABAA

Agonists: (+)-Catechin Bamaluzole Barbiturates
Barbiturates
(e.g., phenobarbital) BL-1020 DAVA Dihydromuscimol GABA Gabamide GABOB Gaboxadol
Gaboxadol
(THIP) Homotaurine
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 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
Barbiturates
(e.g., phenobarbital) Benzodiazepines (e.g., diazepam) Bromide compounds (e.g., potassium bromide) Carbamates
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
Kava
constituents (e.g., kavain) Lanthanum Loreclezole Monastrol Neuroactive steroids (e.g., allopregnanolone, cholesterol) Niacin Nicotinamide
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
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
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 Bilobalide CHEB Cicutoxin Cloflubicyne Cyclothiazide DHEA DHEA-S Dieldrin (+)-DMBB DMCM DMPC EBOB Etbicyphat FG-7142
FG-7142
(ZK-31906) Fiproles (e.g., fipronil) Flavonoids (e.g., amentoflavone, oroxylin A) Flumazenil Fluoroquinolones (e.g., ciprofloxacin) Flurothyl Furosemide Iomazenil (123I) IPTBO Isoallopregnanolone Isopregnanolone
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
Pentylenetetrazol
(pentetrazol) Phenylsilatrane Picrotoxin
Picrotoxin
(i.e., picrotin and picrotoxinin) 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
Gabazine
(SR-95531) Gaboxadol
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
Picrotoxin
(picrotin, picrotoxinin) Pregnanolone ROD-188 THDOC Zinc

Metabotropic

GABAB

Agonists: 1,4-Butanediol 4-Fluorophenibut Aceburic acid Arbaclofen 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
Homotaurine
(tramiprosate, 3-APS) Phaclofen Saclofen SCH-50911 SKF-97541

Negative modulators: Compound 14

See also Receptor/signaling modulators GABAA receptor
GABAA receptor
positive modulators GABA
GABA
metabolism/transport modulators

v t e

GABAA receptor
GABAA receptor
positive modulators

Alcohols

Brometone Butanol Chloralodol Chlorobutanol
Chlorobutanol
(cloretone) Ethanol
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
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
Ampelopsin
(dihydromyricetin) Apigenin Baicalein Baicalin Catechin EGC EGCG Hispidulin Linarin Luteolin Rc-OMe Skullcap constituents (e.g., baicalin) Wogonin

Imidazoles

Etomidate Metomidate Propoxate

Kava
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
Apronal
(apronalide) Bromisoval Carbromal Capuride Ectylurea

Neuroactive steroids

Acebrochol Allopregnanolone
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
Pregnanolone
(eltanolone) Progesterone Renanolone SAGE-105 SAGE-217 SAGE-324 SAGE-516 SAGE-689 SAGE-872 Testosterone THDOC

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
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
Chloral
betaine Chloral
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
Menthyl isovalerate
(validolum) Monastrol Niacin Nicotinamide
Nicotinamide
(niacinamide) Org 25,435 Phenytoin Propanidid Retigabine
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
GABA
receptor modulators • GABA
GABA
metabolism/transpor

.