Barbiturate

Barbituric acid, the basic structure of all barbiturates

A barbiturate^[a] is a drug that acts as a central nervous system depressant, and can therefore produce a wide spectrum of effects, from mild sedation to death. Barbiturates are effective as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential. They have largely been replaced by benzodiazepines in routine medical practice, particularly in the treatment of anxiety and insomnia, due to the significantly lower risk of addiction and overdose and the lack of an antidote for barbiturate overdose. Despite this, barbiturates are still in use for various purposes: in general anesthesia, epilepsy, treatment of acute migraines or cluster headaches, euthanasia, capital punishment, and assisted suicide.^[2]

The name barbiturate originates from the fact that they are all chemical derivatives of barbituric acid.^[3]

Contents

• 
  1 Uses
  
  
  
  • 
    1.1 Medicine
    
  
  
  • 
    1.2 Interrogation
    
  
  
  • 
    1.3 Chemistry
    
  
  
  
  


• 
  2 Side effects
  
  
  
  • 
    2.1 Tolerance and dependence
    
  
  
  • 
    2.2 Overdose
    
  
  
  
  


• 
  3 Mechanism of action
  


• 
  4 History
  


• 
  5 Society and culture
  
  
  
  • 
    5.1 Legal status
    
  
  
  • 
    5.2 Recreational use
    
  
  
  
  


• 
  6 Examples
  


• 
  7 See also
  


• 
  8 Notes
  


• 
  9 References
  


• 
  10 External links and further reading
  

Uses

Medicine

Barbiturates such as phenobarbital were long used as anxiolytics and hypnotics, but today have been largely replaced by benzodiazepines for these purposes because the latter are less toxic in overdose.^[4][5][6] However, barbiturates are still used as anticonvulsants (e.g., phenobarbital and primidone) and general anesthetics (e.g., sodium thiopental).

Barbiturates in high doses are used for physician-assisted suicide, and in combination with a muscle relaxant for euthanasia and for capital punishment by lethal injection.^[7][8] Barbiturates are frequently employed as euthanizing agents in small-animal veterinary medicine.

Interrogation

Sodium thiopental is an ultra-short-acting barbiturate that is marketed under the name Sodium Pentothal. It is often mistaken for "truth serum", or sodium amytal, an intermediate-acting barbiturate that is used for sedation and to treat insomnia, but was also used in so-called sodium amytal "interviews" where the person being questioned would be much more likely to provide the truth whilst under the influence of this drug. When dissolved in water, sodium amytal can be swallowed, or it can be administered by intravenous injection. The drug does not itself force people to tell the truth, but is thought to decrease inhibitions and slow creative thinking, making subjects more likely to be caught off guard when questioned, and increasing the possibility of the subject revealing information through emotional outbursts.^[9]

The memory-impairing effects and cognitive impairments induced by sodium thiopental are thought to reduce a subject's ability to invent and remember lies. This practice is no longer considered legally admissible in court due to findings that subjects undergoing such interrogations may form false memories, putting the reliability of all information obtained through such methods into question. Nonetheless, it is still employed in certain circumstances by defense and law enforcement agencies as a "humane" alternative to torture interrogation when the subject is believed to have information critical to the security of the state or agency employing the tactic.^[10]

Chemistry

In 1988, the synthesis and binding studies of an artificial receptor binding barbiturates by six complementary hydrogen bonds was published.^[11] Since this first article, different kind of receptors were designed, as well as different barbiturates and cyanurates, not for their efficiencies as drugs but for applications in supramolecular chemistry, in the conception of materials and molecular devices.

Sodium barbital and barbital have also been used as pH buffers for biological research, e.g., in immunoelectrophoresis or in fixative solutions.^[12][13]

Side effects

Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Barbiturates were ranked 5th in dependence, 3rd in physical harm, and 4th in social harm.^[14]

There are special risks to consider for older adults, women who are pregnant, and babies. When a person ages, the body becomes less able to rid itself of barbiturates. As a result, people over the age of sixty-five are at higher risk of experiencing the harmful effects of barbiturates, including drug dependence and accidental overdose.^[15] When barbiturates are taken during pregnancy, the drug passes through the placenta to the fetus. After the baby is born, it may experience withdrawal symptoms and have trouble breathing. In addition, nursing mothers who take barbiturates may transmit the drug to their babies through breast milk.^[16] A rare adverse reaction to barbiturates is Stevens-Johnson syndrome, which primarily affects the mucous membranes.

Tolerance and dependence

Main article: Barbiturate dependence

With regular use, tolerance to the effects of barbiturates develops. Research shows that tolerance can develop with even one administration of a barbiturate. As with all GABAergic drugs, barbiturate withdrawal produces potentially fatal effects such as seizures in a manner reminiscent of delirium tremens and benzodiazepine withdrawal although its more direct mechanism of GABA agonism makes barbiturate withdrawal even more severe than that of alcohol or benzodiazepines (subsequently making it one of the most dangerous withdrawals of any known addictive substance). Similarly to benzodiazepines, the longer acting barbiturates produce a less severe withdrawal syndrome than short acting and ultra-short acting barbiturates. Withdrawal symptoms are dose-dependent with heavier users being more affected than lower-dose addicts.

The pharmacological treatment of barbiturate withdrawal is an extended process often consisting of converting the patient to a long-acting benzodiazepine (i.e. Valium), followed by slowly tapering off the benzodiazepine. Mental cravings for barbiturates can last for months or years in some cases and counselling/support groups are highly encouraged by addiction specialists. Patients should never try to tackle the task of discontinuing barbiturates without consulting a doctor due to the high lethality and relatively sudden onset of the withdrawal. Attempting to quit "cold turkey" may result in serious neurological damage, severe physical injuries received during convulsions, and even death via glutamatergic excitotoxicity.

Overdose

Main article: Barbiturate overdose

Some symptoms of an overdose typically include sluggishness, incoordination, difficulty in thinking, slowness of speech, faulty judgement, drowsiness, shallow breathing, staggering, and, in severe cases, coma or death. The lethal dosage of barbiturates varies greatly with tolerance and from one individual to another. The lethal dose is highly variable among different members of the class with superpotent barbiturates such as pentobarbital being potentially fatal in considerably lower doses than the low-potency barbiturates such as butalbital. Even in inpatient settings, however, the development of tolerance is still a problem, as dangerous and unpleasant withdrawal symptoms can result when the drug is stopped after dependence has developed. Tolerance to the anxiolytic and sedative effects of barbiturates tends to develop faster than tolerance to their effects on smooth muscle, respiration, and heart rate, making them generally unsuitable for a long time psychiatric use. Tolerance to the anticonvulsant effects tends to correlate more with tolerance to physiological effects, however, meaning that they are still a viable option for long-term epilepsy treatment.

Barbiturates in overdose with other CNS (central nervous system) depressants (e.g. alcohol, opiates, benzodiazepines) are even more dangerous due to additive CNS and respiratory depressant effects. In the case of benzodiazepines, not only do they have additive effects, barbiturates also increase the binding affinity of the benzodiazepine binding site, leading to exaggerated benzodiazepine effects. (ex. If a benzodiazepine increases the frequency of channel opening by 300%, and a barbiturate increases the duration of their opening by 300%, then the combined effects of the drugs increase the channels overall function by 900%, not 600%).

The longest-acting barbiturates have half-lives of a day or more, and subsequently result in bioaccumulation of the drug in the system. The therapeutic and recreational effects of long-acting barbiturates wear off significantly faster than the drug can be eliminated, allowing the drug to reach toxic concentrations in the blood following repeated administration (even when taken at the therapeutic/prescribed dose) despite the user feeling little or no effects from the plasma-bound concentrations of the drug. Users who consume alcohol or other sedatives after the drugs effects have worn but before it has cleared the system may experience a greatly exaggerated effect from the other sedatives which can be incapacitating or even fatal.

Barbiturates induce a number of hepatic CYP enzymes (most notably CYP2C9, CYP2C19 and CYP3A4),^[17] leading to exaggerated effects from many prodrugs and decreased effects from drugs which are metabolized by these enzymes to inactive metabolites. This can result in fatal overdoses from drugs such as codeine, tramadol, and carisoprodol, which become considerably more potent after being metabolized by CYP enzymes. Although all known members of the class possess relevant enzyme induction capabilities the degree of inhibition overall as well as the impact on each specific enzyme span a broad range with phenobarbital and secobarbital being the most potent enzyme inducers and butalbital and talbutal being among the weakest enzyme inducers in the class.

People who are known to have killed themselves with a barbiturate overdose include Charles Boyer, Dalida, Phyllis Hyman, Lupe Velez, Carole Landis, Jean Seberg, Abbie Hoffman, Felix Hausdorff and C. P. Ramanujam. Others who have died as a result of barbiturate overdose include Judy Garland, Marilyn Monroe, Ellen Wilkinson, Dorothy Kilgallen, Pier Angeli, Brian Epstein, Alan Wilson, Jimi Hendrix, Thalia Massie, Edie Sedgwick, Inger Stevens and Kenneth Williams; in some cases these have been speculated to be suicides as well. Dorothy Dandridge died of either an overdose or an unrelated embolism. Ingeborg Bachmann may have died of the consequences of barbiturate withdrawal (she was hospitalized with burns, the doctors treating her not being aware of her Barbiturate addiction).

Mechanism of action

Barbiturates act as positive allosteric modulators, and at higher doses, as agonists of GABA_A receptors.^[18]GABA is the principal inhibitory neurotransmitter in the mammalian central nervous system (CNS). Barbiturates bind to the GABA_A receptor at multiple homologous transmembrane pockets located at subunit interfaces,^[19] which are binding sites distinct from GABA itself and also distinct from the benzodiazepine binding site. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. In addition to this GABAergic effect, barbiturates also block AMPA and kainate receptors, subtypes of ionotropic glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Taken together, the findings that barbiturates potentiate inhibitory GABA_A receptors and inhibit excitatory AMPA receptors can explain the superior CNS-depressant effects of these agents to alternative GABA potentiating agents such as benzodiazepines and quinazolinones. At higher concentration, they inhibit the Ca²⁺-dependent release of neurotransmitters such as glutamate via an effect on P/Q-type voltage-dependent calcium channels.^[20]
Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABA_A receptor (pharmacodynamics: This increases the efficacy of GABA), whereas benzodiazepines increase the frequency of the chloride ion channel opening at the GABA_A receptor (pharmacodynamics: This increases the potency of GABA). The direct gating or opening of the chloride ion channel is the reason for the increased toxicity of barbiturates compared to benzodiazepines in overdose.^[21][22]

Further, barbiturates are relatively non-selective compounds that bind to an entire superfamily of ligand-gated ion channels, of which the GABA_A receptor channel is only one of several representatives. This Cys-loop receptor superfamily of ion channels includes the neuronal nACh receptor channel, the 5-HT₃ receptor channel, and the glycine receptor channel. However, while GABA_A receptor currents are increased by barbiturates (and other general anaesthetics), ligand-gated ion channels that are predominantly permeable for cationic ions are blocked by these compounds. For example, neuronal nAChR channels are blocked by clinically relevant anaesthetic concentrations of both thiopental and pentobarbital.^[23] Such findings implicate (non-GABA-ergic) ligand-gated ion channels, e.g. the neuronal nAChR channel, in mediating some of the (side) effects of barbiturates.^[24] This is the mechanism responsible for the (mild to moderate) anesthetic effect of barbiturates in high doses when used in anesthetic concentration.

History

Barbituric acid was first synthesized November 27, 1864, by German chemist Adolf von Baeyer. This was done by condensing urea (an animal waste product) with diethyl malonate (an ester derived from the acid of apples). There are several stories about how the substance got its name. The most likely story is that Baeyer and his colleagues went to celebrate their discovery in a tavern where the town's artillery garrison were also celebrating the feast of Saint Barbara – the patron saint of artillerymen. An artillery officer is said to have christened the new substance by amalgamating Barbara with urea.^[25] Another story holds that Baeyer synthesized the substance from the collected urine of a Munich waitress named Barbara.^[26] No substance of medical value was discovered, however, until 1903 when two German scientists working at Bayer, Emil Fischer and Joseph von Mering, discovered that barbital was very effective in putting dogs to sleep. Barbital was then marketed by Bayer under the trade name Veronal. It is said that Mering proposed this name because the most peaceful place he knew was the Italian city of Verona.^[25]

It was not until the 1950s that the behavioural disturbances and physical dependence potential of barbiturates became recognized.^[27]

Barbituric acid itself does not have any direct effect on the central nervous system and chemists have derived over 2,500 compounds from it that possess pharmacologically active qualities. The broad class of barbiturates is further broken down and classified according to speed of onset and duration of action. Ultrashort-acting barbiturates are commonly used for anesthesia because their extremely short duration of action allows for greater control. These properties allow doctors to rapidly put a patient "under" in emergency surgery situations. Doctors can also bring a patient out of anesthesia just as quickly, should complications arise during surgery. The middle two classes of barbiturates are often combined under the title "short/intermediate-acting." These barbiturates are also employed for anesthetic purposes, and are also sometimes prescribed for anxiety or insomnia. This is not a common practice anymore, however, owing to the dangers of long-term use of barbiturates; they have been replaced by the benzodiazepines for these purposes. The final class of barbiturates are known as long-acting barbiturates (the most notable one being phenobarbital, which has a half-life of roughly 92 hours). This class of barbiturates is used almost exclusively as anticonvulsants, although on rare occasions they are prescribed for daytime sedation. Barbiturates in this class are not used for insomnia, because, owing to their extremely long half-life, patients would awake with a residual "hang-over" effect and feel groggy.

Barbiturates can in most cases be used either as the free acid or as salts of sodium, calcium, potassium, magnesium, lithium, etc. Codeine- and Dionine-based salts of barbituric acid have been developed. In 1912, Bayer introduced another barbituric acid derivative, phenobarbital, under the trade name Luminal, as a sedative-hypnotic.^[28]

Society and culture

Legal status

During World War II, military personnel in the Pacific region were given "goofballs" to allow them to tolerate the heat and humidity of daily working conditions. Goofballs were distributed to reduce the demand on the respiratory system, as well as maintaining blood pressure, to combat the extreme conditions. Many soldiers returned with addictions that required several months of rehabilitation before discharge. This led to growing dependency problems, often exacerbated by indifferent doctors prescribing high doses to unknowing patients through the 1950s and 1960s.^{[citation needed]}

In the late 1950s and 1960s, an increasing number of published reports of barbiturate overdoses and dependence problems led physicians to reduce their prescription, particularly for spurious requests. This eventually led to the scheduling of barbiturates as controlled drugs.

In the Netherlands, the Opium Law classifies all barbiturates as List II drugs, with the exception of secobarbital, which is on List I.

There is a small group of List II drugs for which doctors have to write the prescriptions according to the same, tougher guidelines as those for List I drugs (writing the prescription in full in letters, listing the patients name, and have to contain the name and initials, address, city and telephone number of the licensed prescriber issuing the prescriptions, as well as the name and initials, address and city of the person the prescription is issued to). Among that group of drugs are the barbiturates amobarbital, butalbital, cyclobarbital, and pentobarbital.

In the United States, the Controlled Substances Act of 1970 classified most barbiturates as controlled substances—and they remain so as of September 2015^[update]. Barbital, methylphenobarbital (also known as mephobarbital), and phenobarbital are designated schedule IV drugs, and "Any substance which contains any quantity of a derivative of barbituric acid, or any salt of a derivative of barbituric acid"^[29] (all other barbiturates) were designated as being schedule III. Under the original CSA, no barbiturates were placed in schedule I, II, or V,^[30] however amobarbital, pentobarbital, and secobarbital are schedule II controlled substances unless they are in a suppository dosage form.^[31]

In 1971, the Convention on Psychotropic Substances was signed in Vienna. Designed to regulate amphetamines, barbiturates, and other synthetics, the 34th version of the treaty, as of 25 January 2014^[update], regulates secobarbital as schedule II, amobarbital, butalbital, cyclobarbital, and pentobarbital as schedule III, and allobarbital, barbital, butobarbital, mephobarbital, phenobarbital, butabarbital, and vinylbital as schedule IV on its "Green List".^[32] The combination medication Fioricet, consisting of butalbital, caffeine, and paracetamol (acetaminophen), however, is specifically exempted from controlled substance status, while its sibling Fiorinal, which contains aspirin instead of paracetamol and may contain codeine phosphate, remains a schedule III drug.

Recreational use

Recreational users report that a barbiturate high gives them feelings of relaxed contentment and euphoria. Physical and psychological dependence may also develop with repeated use.^[33] Chronic misuse of barbiturates is associated with significant morbidity. One study found that 11% of males and 23% of females with a sedative-hypnotic misuse die by suicide.^[34] Other effects of barbiturate intoxication include drowsiness, lateral and vertical nystagmus, slurred speech and ataxia, decreased anxiety and loss of inhibitions. Barbiturates are also used to alleviate the adverse or withdrawal effects of illicit drug use, in a manner similar to long-acting benzodiazepines such as diazepam and clonazepam.^[35][36] Often poly drug abuse occurs: Barbiturates are consumed with or substituted by other available substances, most commonly alcohol.

Drug users tend to prefer short-acting and intermediate-acting barbiturates.^[37] The most commonly used are amobarbital (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal). A combination of amobarbital and secobarbital (called Tuinal) is also highly used. Short-acting and intermediate-acting barbiturates are usually prescribed as sedatives and sleeping pills. These pills begin acting fifteen to forty minutes after they are swallowed, and their effects last from five to six hours.

Slang terms for barbiturates include barbs, bluebirds, dolls, wallbangers, yellows, downers, goofballs, sleepers, 'reds & blues' and tooties.^[38]

Examples

Generic structure of a barbiturate, including numbering scheme

Barbiturates

Short Name	R1	R2	IUPAC Name
allobarbital	CH2CHCH2	CH2CHCH2	5,5-diallylbarbiturate
amobarbital[39]	CH2CH3	(CH2)2CH(CH3)2	5-ethyl-5-isopentyl-barbiturate
aprobarbital	CH2CHCH2	CH(CH3)2	5-allyl-5-isopropyl-barbiturate
alphenal	CH2CHCH2	C6H5	5-allyl-5-phenyl-barbiturate
barbital	CH2CH3	CH2CH3	5,5-diethylbarbiturate
brallobarbital	CH2CHCH2	CH2CBrCH2	5-allyl-5-(2-bromo-allyl)-barbiturate
pentobarbital[39]	CH2CH3	CHCH3(CH2)2CH3	5-ethyl-5-(1-methylbutyl)-barbiturate
phenobarbital[39]	CH2CH3	C6H5	5-ethyl-5-phenylbarbiturate
secobarbital[39]	CH2CHCH2	CHCH3(CH2)2CH3	5-[(2R)-pentan-2-yl]-5-prop-2-enyl-barbiturate; 5-allyl-5-[(2R)-pentan-2-yl]-barbiturate

Thiopental is a barbiturate with one of the C-O double bonds (with the carbon being labelled 2 in the adjacent diagram) replaced with a C-S double bond, R¹ being CH₂CH₃ and R² being CH(CH₃)CH₂CH₂CH₃.

See also

• 
  Pharmacy and Pharmacology portal
  

• Benzodiazepines


• Psycholeptic


• The Dille–Koppanyi reagent, used as a spot test for barbiturates.


• The Zwikker reagent, also used as a spot test for barbiturates.

Notes

1. 
   ^ The most often cited standard pronunciation is /ˌbɑːrˈbɪtjʊrɪt/; however, at least in the U.S., the more commonly used colloquial pronunciation is /ˌbɑːrˈbɪtjuɪt/.^[1]
   

References

1. 
   ^ Vaux, Bert and Scott Golder. 2003. The Harvard Dialect Survey. Cambridge, MA: Harvard University Linguistics Department.
   


2. 
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11. 
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29. 
    ^ Pub. L. 91-513, October 27, 1970, Sec. 202(c) Sched. III(b)(1)
    


30. 
    ^ 21 U.S.C. § 812
    


31. 
    ^ 21 U.S.C. § §1308.12
    


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External links and further reading

Look up barbiturate in Wiktionary, the free dictionary.

• 
  U.S. Drug Enforcement Administration Source for some public domain text used on this page.


• 
  López-Muñoz, F.; Ucha-Udabe, R.; Alamo, C. (2005). "The history of barbiturates a century after their clinical introduction". Neuropsychiatric Disease and Treatment. 1 (4): 329–343. PMC 2424120. PMID 18568113.
  


• 
  National Institute on Drug Abuse: "NIDA for Teens: Prescription Depressant Medications".

v t e Treatment of drug dependence (N07B)
Nicotine dependence	Bupropion Cytisine Lobeline Mecamylamine Varenicline AA (Clonidine)
Alcohol dependence	AD inhibitor (Disulfiram Calcium carbimide Hydrogen cyanamide) Acamprosate Opioid antagonists (Naltrexone Nalmefene) Topiramate AA (Clonidine) Baclofen Metadoxine Phenibut
Opioid dependence	AA (Clonidine Lofexidine) Ibogaine Opioids Buprenorphine (+naloxone) Levacetylmethadol Methadone Dihydrocodeine Dihydroetorphine Hydromorphone (extended-release) Morphine (extended-release) Opioid antagonists (Naltrexone Nalmefene)
Benzodiazepine dependence	AA (Clonidine) Benzodiazepines (Diazepam Lorazepam Chlordiazepoxide Oxazepam) Barbiturates (Phenobarbital)
Research	Salvia divinorum

v t e Anticonvulsants (N03)
GABAergics	GABAAR PAMs Barbiturates: Barbexaclone Metharbital Methylphenobarbital Pentobarbital Phenobarbital# Primidone; Carbamates: Felbamate; Benzodiazepines: Clobazam Clonazepam Clorazepate Diazepam# Lorazepam# Midazolam Nimetazepam Nitrazepam Temazepam; Others: Bromide (potassium bromide, sodium bromide) Imepitoin Paraldehyde Stiripentol GABA-T inhibitors Fatty acids (and related): Valproate Valpromide Valproate pivoxil Vigabatrin Others GABAR agonists: Progabide; GAT-1 inhibitors: Tiagabine
Channel modulators	Sodium blockers Hydantoins: Ethotoin Fosphenytoin Mephenytoin Phenytoin#; Ureides: Acetylpheneturide Chlorphenacemide Phenacemide‡ Pheneturide; Fatty acids: Valproate Valpromide Valproate pivoxil; Carboxamides: Carbamazepine# Eslicarbazepine acetate Oxcarbazepine; Others: Lacosamide Lamotrigine# Rufinamide Topiramate Zonisamide Calcium blockers Oxazolidinediones: Ethadione Paramethadione Trimethadione; Succinimides: Ethosuximide# Mesuximide Phensuximide; Gabapentinoids: Gabapentin Pregabalin; Others: Imepitoin Lamotrigine# Topiramate Zonisamide Potassium openers Retigabine
Others	CA inhibitors Sulfonamides: Acetazolamide Ethoxzolamide Sultiame Topiramate Zonisamide Others Albutoin Beclamide Brivaracetam Cannabidiol Etiracetam Levetiracetam Perampanel
#WHO-EM ‡Withdrawn from market Clinical trials: †Phase III §Never to phase III

v t e Anxiolytics (N05B)
5-HT1AR agonists	Buspirone Gepirone† Tandospirone
GABAAR PAMs	Benzodiazepines: Adinazolam Alprazolam Bromazepam Camazepam Chlordiazepoxide Clobazam Clonazepam Clorazepate Clotiazepam Cloxazolam Diazepam# Ethyl loflazepate Etizolam Fludiazepam Halazepam Ketazolam Lorazepam# Medazepam Nordazepam Oxazepam Pinazepam Prazepam; Others: Alpidem‡ Barbiturates (e.g., phenobarbital) Carbamates (e.g., meprobamate) Chlormezanone‡ Ethanol (alcohol) Etifoxine Imepitoin; Herbs: Kava Skullcap Valerian
Gabapentinoids (α2δ VDCC blockers)	Gabapentin Gabapentin enacarbil Phenibut Pregabalin
Antidepressants	SSRIs (e.g., escitalopram) SNRIs (e.g., duloxetine) SARIs (e.g., trazodone) TCAs (e.g., clomipramine#) TeCAs (e.g., mirtazapine) MAOIs (e.g., phenelzine); Others: Agomelatine Bupropion Tianeptine Vilazodone Vortioxetine
Sympatholytics (Antiadrenergics)	Alpha-1 blockers (e.g., prazosin) Alpha-2 agonists (e.g., clonidine, dexmedetomidine, guanfacine) Beta blockers (e.g., propranolol)
Others	Benzoctamine Cannabidiol Cycloserine Fabomotizole Hydroxyzine Kanna Lavender Lorpiprazole Mebicar Mepiprazole Nicotine Opipramol Oxaflozane‡ Phenaglycodol Phenibut Picamilon Selank Tiagabine Tofisopam Validolum
#WHO-EM ‡Withdrawn from market Clinical trials: †Phase III §Never to phase III

v t e Hypnotics/sedatives (N05C)
GABAA	Alcohols 2M2B Chloralodol Ethanol (alcohol) Ethchlorvynol Methylpentynol Trichloroethanol Barbiturates Allobarbital Amobarbital Aprobarbital Barbital Butabarbital Butobarbital Cyclobarbital Ethallobarbital Heptabarb Hexobarbital Mephobarbital Methohexital Narcobarbital Pentobarbital Phenallymal Phenobarbital Propylbarbital Proxibarbal Reposal Secobarbital Talbutal Thiamylal Thiopental Thiotetrabarbital Vinbarbital Vinylbital Benzodiazepines Brotizolam Cinolazepam Climazolam Doxefazepam Estazolam Flunitrazepam Flurazepam Flutoprazepam Lorazepam Loprazolam Lormetazepam Midazolam Nimetazepam Nitrazepam Phenazepam Quazepam Temazepam Triazolam Carbamates Carisoprodol Emylcamate Ethinamate Hexapropymate Meprobamate Methocarbamol Phenprobamate Procymate Tybamate Imidazoles Etomidate Metomidate Propoxate Monoureides Acecarbromal Apronal (apronalide) Bromisoval Capuride Carbromal Ectylurea Neuroactive steroids Acebrochol Allopregnanolone Alphadolone Alphaxolone Eltanolone Hydroxydione Minaxolone Progesterone Nonbenzodiazepines Eszopiclone Indiplon Lirequinil Necopidem Pazinaclone Saripidem Suproclone Suriclone Zaleplon Zolpidem Zopiclone Phenols Propofol Piperidinediones Glutethimide Methyprylon Pyrithyldione Piperidione Quinazolinones Afloqualone Cloroqualone Diproqualone Etaqualone Mebroqualone Mecloqualone Methaqualone Methylmethaqualone Nitromethaqualone Others Acetophenone Acetylglycinamide chloral hydrate Bromide compounds Lithium bromide Potassium bromide Sodium bromide Centalun Chloral betaine Chloral hydrate Chloralose Clomethiazole Dichloralphenazone Gaboxadol Kavalactones Loreclezole Paraldehyde Petrichloral Sulfonylalkanes Sulfonmethane (sulfonal) Tetronal Trional Triclofos Sesquiterpene Isovaleramide Isovaleric acid Valerenic acid
GABAB	1,4-Butanediol 4-Fluorophenibut Aceburic acid Baclofen GABOB GHB (sodium oxybate) GBL GVL Phenibut Tolibut
H1	Antihistamines Captodiame Cyproheptadine Diphenhydramine Doxylamine Hydroxyzine Methapyrilene Perlapine Pheniramine Promethazine Propiomazine Antidepressants Serotonin antagonists and reuptake inhibitors Etoperidone Nefazodone Trazodone Tricyclic antidepressants Amitriptyline Doxepin Trimipramine, etc. Tetracyclic antidepressants Mianserin Mirtazapine, etc. Antipsychotics Typical antipsychotics Chlorpromazine Thioridazine, etc. Atypical antipsychotics Olanzapine Quetiapine Risperidone, etc.
α2-Adrenergic	Clonidine Detomidine Dexmedetomidine Lofexidine Medetomidine Romifidine Tizanidine Xylazine
5-HT2A	Antidepressants Trazodone Tricyclic antidepressants Amitriptyline Doxepin Trimipramine, etc. Tetracyclic antidepressants Mianserin Mirtazapine, etc. Antipsychotics Typical antipsychotics Chlorpromazine Thioridazine, etc. Atypical antipsychotics Olanzapine Quetiapine Risperidone, etc. Others Niaprazine
Melatonin	Agomelatine Melatonin Ramelteon Tasimelteon
Orexin	Almorexant Filorexant Suvorexant
α2δ VDCC	Gabapentin Gabapentin enacarbil Mirogabalin Phenibut Pregabalin
Others	Cannabidiol Cannabis Chlorophenylalkyldiols Fenpentadiol Metaglycodol Phenaglycodol Diethylpropanediol Evoxine Fenadiazole Guaifenesin-related muscle relaxants Chlorphenesin Mephenesin Mephenoxalone Metaxalone Methocarbamol Opioids (e.g., morphine) Passion flower Scopolamine Trazodone UMB68 Valnoctamide

v t e Insomnia pharmacotherapies
GABAAR PAMs	Benzodiazepines: Brotizolam Cinolazepam Climazolam Clorazepate Doxefazepam Estazolam Etizolam Flunitrazepam Flurazepam Flutoprazepam Haloxazolam Loprazolam Lormetazepam Midazolam Nimetazepam Nitrazepam Quazepam Temazepam Triazolam; Nonbenzodiazepines/Z-drugs: Eszopiclone Zaleplon Zolpidem Zopiclone; Others: Alcohols (e.g., ethchlorvynol, amylene hydrate, ethanol) Barbiturates (e.g., amobarbital, pentobarbital, phenobarbital, secobarbital) Bromides (e.g., potassium bromide, sodium bromide) Carbamates (e.g., meprobamate) Chloral hydrate Clomethiazole Kava Paraldehyde Piperidinediones (e.g., glutethimide) Quinazolinones (e.g., methaqualone) Sulfonmethane Valerian
Antihistamines (H1R inverse agonists)	Alimemazine Captodiame Dimenhydrinate Diphenhydramine Doxylamine Etodroxizine Hydroxyzine Meclizine Methapyrilene Pheniramine Phenyltoloxamine Pimethixene Promethazine Propiomazine Pyrilamine TCAs (e.g., amitriptyline, doxepin, trimipramine) TeCAs (e.g., mirtazapine) Triprolidine
OXR antagonists	Almorexant§ Filorexant§ Lemborexant§ Suvorexant
MTR agonists	Agomelatine Melatonin Ramelteon Tasimelteon
Miscellaneous	Antipsychotics (e.g., quetiapine, olanzapine, chlorpromazine) Ashwagandha Benzoctamine Cannabinoids (e.g., cannabis, dronabinol (THC), nabilone) Chamomile Fenadiazole Gabapentinoids (e.g., gabapentin, pregabalin, phenibut) Hops Lavender Menthyl isovalerate Niaprazine Opioids (e.g., hydrocodone, oxycodone, morphine) Passion flower Scopolamine Serotonin precursors (tryptophan, 5-HTP) Sodium oxybate (GHB) Sympatholytics (e.g., clonidine, guanfacine) TCAs (e.g., amitriptyline, doxepin, trimipramine) TeCAs (e.g., mirtazapine) Theanine Trazodone Valnoctamide

Pharmacodynamics

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-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 (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 v t e Glycine receptor modulators Receptor (ligands) GlyR Agonists: β-Alanine β-ABA (BABA) β-AIBA Caesium D-Alanine D-Serine GABA Glycine Hypotaurine Ivermectin L-Alanine L-Proline L-Serine L-Threonine MDL-27531 Milacemide Picolinic acid Propofol Quisqualamine Sarcosine Taurine Positive modulators: Alcohols (e.g., brometone, chlorobutanol (chloretone), ethanol (alcohol), tert-butanol (2M2P), tribromoethanol, trichloroethanol, trifluoroethanol) Alkylbenzene sulfonate Anandamide Barbiturates (e.g., pentobarbital, sodium thiopental) Chlormethiazole D12-116 Dihydropyridines (e.g., nicardipine) Etomidate Ginseng constituents (e.g., ginsenosides (e.g., ginsenoside-Rf)) Glutamic acid (glutamate) Ivermectin Ketamine Neuroactive steroids (e.g., alfaxolone, pregnenolone (eltanolone), pregnenolone acetate, minaxolone, ORG-20599) Nitrous oxide Penicillin G Propofol Tamoxifen Tetrahydrocannabinol Triclofos Tropeines (e.g., atropine, bemesetron, cocaine, LY-278584, tropisetron, zatosetron) Volatiles/gases (e.g., chloral hydrate, chloroform, desflurane, diethyl ether (ether), enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, toluene, trichloroethane (methyl chloroform), trichloroethylene) Xenon Zinc Antagonists: 2-Aminostrychnine 2-Nitrostrychnine 4-Phenyl-4-formyl-N-methylpiperidine αEMBTL Bicuculline Brucine Cacotheline Caffeine Colchicine Colubrine Cyanotriphenylborate Dendrobine Diaboline Endocannabinoids (e.g., 2-AG, anandamide (AEA)) Gaboxadol (THIP) Gelsemine iso-THAZ Isobutyric acid Isonipecotic acid Isostrychnine Laudanosine N-Methylbicuculline N-Methylstrychnine N,N-Dimethylmuscimol Nipecotic acid Pitrazepin Pseudostrychnine Quinolines (e.g., 4-hydroxyquinoline, 4-hydroxyquinoline-3-carboxylic acid, 5,7-CIQA, 7-CIQ, 7-TFQ, 7-TFQA) RU-5135 Sinomenine Strychnine Thiocolchicoside Tutin Negative modulators: Amiloride Benzodiazepines (e.g., bromazepam, clonazepam, diazepam, flunitrazepam, flurazepam) Corymine Cyanotriphenylborate Daidzein Dihydropyridines (e.g., nicardipine, nifedipine, nitrendipine) Furosemide Genistein Ginkgo constituents (e.g., bilobalide, ginkgolides (e.g., ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide M)) Imipramine NBQX Neuroactive steroids (e.g., 3α-androsterone sulfate, 3β-androsterone sulfate, deoxycorticosterone, DHEA sulfate, pregnenolone sulfate, progesterone) Opioids (e.g., codeine, dextromethorphan, dextrorphan, levomethadone, levorphanol, morphine, oripavine, pethidine, thebaine) Picrotoxin (i.e., picrotin and picrotoxinin) PMBA Riluzole Tropeines (e.g., bemesetron, LY-278584, tropisetron, zatosetron) Verapamil Zinc NMDAR See here instead. Transporter (blockers) GlyT1 ACPPB ALX-1393 ALX-5407 (NFPS) AMG-747 ASP2535 BIIB-104 (PF-04958242) Bitopertin (RG1678/RO4917838) CP-802079 Ethanol (alcohol) Glycyldodecylamide GSK1018921 LY-2365109 ORG-24598 ORG-25935 (SCH-900435) PF-02545920 PF-03463275 Sarcosine SSR-103,800 SSR-504,734 GlyT2 Amoxapine Ethanol (alcohol) NAGly Opiranserin (VVZ-149) ORG-25543 VVZ-368 See also Receptor/signaling modulators GABA receptor modulators GABAA receptor positive modulators Ionotropic glutamate receptor modulators v t e Ion channel modulators Calcium VDCCs Blockers L-type-selective: Dihydropyridines: Amlodipine Aranidipine Azelnidipine Barnidipine Clevidipine Cronidipine Darodipine Dexniguldipine Elgodipine Elnadipine Felodipine Flordipine Furnidipine Iganidipine Isradipine Lacidipine Lemildipine Lercanidipine Levamlodipine Levniguldipine Manidipine Mepirodipine Mesudipine Nicardipine Nifedipine Niguldipine Niludipine Nilvadipine Nimodipine Nisoldipine Nitrendipine Olradipine Oxodipine Palonidipine Pranidipine Ryodipine (riodipine) Sagandipine Sornidipine Teludipine Tiamdipine Trombodipine Vatanidipine; Diltiazem derivatives: Clentiazem Diltiazem Iprotiazem Nictiazem Siratiazem; Phenylalkylamines: Anipamil Dagapamil Devapamil Dexverapamil Emopamil Etripamil Falipamil Gallopamil Levemopamil Nexopamil Norverapamil Ronipamil Tiapamil Verapamil; Others: AH-1058 Brinazarone Budiodarone Celivarone Cyproheptadine Dronedarone Fantofarone SR-33805 Tetrahydropalmatine N-type-selective: ω-Conotoxins ω-Conotoxin GVIA Caroverine Huwentoxin XVI Leconotide (ω-conotoxin CVID) PD-173212 Ralfinamide Safinamide Z160 Ziconotide (ω-conotoxin MVIIA) P-type-selective: ω-Agatoxin IVA ω-Agatoxin IVB R-type-selective: SNX-482 T-type-selective: ABT-639 ML-218 Niflumic acid NNC 55-0396 ProTx I Z944 Zonisamide Non-selective: ω-Agatoxin TK ω-Conotoxin MVIIC Benidipine Bepridil Cilnidipine Cinnarizine Dotarizine Efonidipine Flunarizine Lamotrigine Levetiracetam Lomerizine Loperamide Mibefradil NP078585 Ruthenium red TROX-1 α2δ subunit-selective (gabapentinoids): 4-Methylpregabalin Arbaclofen Arbaclofen placarbil Atagabalin Baclofen Gabapentin Gabapentin enacarbil Imagabalin Mirogabalin PD-200,347 PD-217,014 PD-299,685 Phenibut Pregabalin Others/unsorted: Bencyclane Berbamine Bevantolol Canadine Carboxyamidotriazole Cycleanine Dauricine Dimeditiapramine Diproteverine Enpiperate Eperisone Elpetrigine Ethadione Ethanol (alcohol) Ethosuximide Fasudil Fendiline Fostedil Imepitoin JTV-519 Lidoflazine Magnesium Manoalide Mesuximide Monatepil Naftopidil Ochratoxin A Osthol Otilonium bromide Paramethadione Phensuximide Pinaverium bromide Prenylamine Rhynchophylline Sesamodil Silperisone Sipatrigine Terodiline Tetrandrine Tolperisone Trimethadione Valperinol Activators L-type-selective: Bay K8644 Potassium VGKCs Blockers 3,4-Diaminopyridine (amifampridine) 4-Aminopyridine (fampridine/dalfampridine) Adekalant Almokalant Amiodarone Azimilide Bretylium Bunaftine Charybdotoxin Clamikalant Conotoxins Dalazatide Dendrotoxin Dofetilide Dronedarone E-4031 Hanatoxin HgeTx1 HsTx1 Ibutilide Inakalant Kaliotoxin Linopirdine Lolitrem B Maurotoxin Nifekalant Notoxin Paxilline Pinokalant Quinidine ShK-186 Sotalol Tedisamil Terikalant Tetraethylammonium Vernakalant hERG (KCNH2, Kv11.1)-specific: Ajmaline Amiodarone AmmTX3 Astemizole Azaspiracid AZD1305 Azimilide Bedaquiline BeKm-1 BmTx3 BRL-32872 Chlorpromazine Cisapride Clarithromycin Darifenacin Dextropropoxyphene Diallyl trisulfide Domperidone E-4031 Ergtoxins Erythromycin Gigactonine Haloperidol Ketoconazole Norpropoxyphene Orphenadrine Pimozide PNU-282,987 Promethazine Quinidine Ranolazine Roxithromycin Sertindole Solifenacin Tamulotoxin Terodiline Terfenadine Thioridazine Tolterodine Vanoxerine Vernakalant KCNQ (Kv7)-specific: Linopirdine XE-991 Spooky toxin (SsTx) Activators KCNQ (Kv7)-specific: Flupirtine Retigabine IRKs Blockers KATP-specific: Acetohexamide Carbutamide Chlorpropamide Glibenclamide (glyburide) Glibornuride Glicaramide Gliclazide Glimepiride Glipizide Gliquidone Glisoxepide Glyclopyramide Glycyclamide Metahexamide Mitiglinide Nateglinide Repaglinide Tolazamide Tolbutamide GIRK-specific: Barium Caramiphen Cloperastine Clozapine Dextromethorphan Ethosuximide Ifenprodil Tertiapin Tipepidine Activators KATP-specific: Aprikalim Bimakalim Cromakalim Diazoxide Emakalim Levcromakalim Mazokalim Minoxidil Naminidil Nicorandil Pinacidil Rilmakalim Sarakalim GIRK-specific: ML-297 (VU0456810) KCa Blockers BKCa-specific: Ethanol (alcohol) GAL-021 Activators BKCa-specific: Flufenamic acid Meclofenamic acid Niflumic acid Nimesulide Rottlerin (mallotoxin) Tolfenamic acid K2Ps Blockers 12-O-Tetradecanoylphorbol-13-acetate Arachidonic acid Fluoxetine Norfluoxetine Activators Riluzole Sodium VGSCs Blockers Antianginals: Ranolazine Antiarrhythmics (class I): Ajmaline Aprindine Disopyramide Dronedarone Encainide Flecainide Lidocaine Lorajmine Lorcainide Mexiletine Moricizine Pilsicainide Prajmaline Procainamide Propafenone Quinidine Sparteine Tocainide Anticonvulsants: Acetylpheneturide Carbamazepine Cenobamate Chlorphenacemide Elpetrigine Eslicarbazepine acetate Ethotoin Fosphenytoin Lacosamide Licarbazepine Mephenytoin Oxcarbazepine Oxitriptyline Phenacemide Pheneturide Phenytoin Rufinamide Sipatrigine Topiramate Sodium valproate Valnoctamide Valproate pivoxil Valproate semisodium Valproic acid Valpromide Zonisamide Local anesthetics: pFBT Amylocaine Articaine Benzocaine Bupivacaine (Levobupivacaine, Ropivacaine) Butacaine Butamben Chloroprocaine Cinchocaine Cocaine Cyclomethycaine Dimethocaine Diphenhydramine Etidocaine Hexylcaine Iontocaine Lidocaine Mepivacaine Meprylcaine Metabutoxycaine Orthocaine Piperocaine Prilocaine Procaine Propoxycaine Proxymetacaine Risocaine Tetracaine Trimecaine Analgesics: AZD-3161 DSP-2230 Funapide GDC-0276 NKTR-171 PF-04531083 PF-05089771 Ralfinamide Raxatrigine RG7893 (GDC-0287) Toxins: Conotoxins Neosaxitoxin Saxitoxin Tetrodotoxin Zetekitoxin AB Others: Buprenorphine Evenamide Menthol (mint) Safinamide Tricyclic antidepressants Activators Aconitine Atracotoxins (Robustoxin, Versutoxin) Batrachotoxin Ciguatoxins Grayanotoxins Poneratoxin ENaC Blockers Amiloride Benzamil Triamterene Activators Solnatide ASICs Blockers A-317567 Amiloride Aspirin Ibuprofen PcTX1 Chloride CaCCs Blockers Crofelemer DIDS Ethacrynic acid Flufenamic acid Fluoxetine Furosemide Glibenclamide Mefloquine Mibefradil Niflumic acid Activators Carbachol CFTR Blockers Glibenclamide Lonidamine Piretanide Activators 1,7-Phenanthroline 1,10-Phenanthroline 4,7-Phenanthroline 7,8-Benzoquinoline Ivacaftor Phenanthridine Unsorted Blockers Bumetanide Flufenamic acid Meclofenamic acid Mefenamic acid Mepacrine Niflumic acid Talniflumate Tolfenamic acid Trifluoperazine Others TRPs See here instead. See also: Receptor/signaling modulators • Transient receptor potential channel modulators v t e Ionotropic glutamate receptor modulators AMPAR Agonists: Main site agonists: 5-Fluorowillardiine Acromelic acid (acromelate) AMPA BOAA Domoic acid Glutamate Ibotenic acid Proline Quisqualic acid Willardiine; Positive allosteric modulators: Aniracetam BIIB-104 (PF-04958242) Cyclothiazide CX-516 CX-546 CX-614 Farampator (CX-691, ORG-24448) CX-717 CX-1739 CX-1942 Diazoxide Hydrochlorothiazide (HCTZ) IDRA-21 LY-392098 LY-395153 LY-404187 LY-451646 LY-503430 Mibampator (LY-451395) Nooglutyl ORG-26576 Oxiracetam PEPA Piracetam Pramiracetam S-18986 Tulrampator (S-47445, CX-1632) Antagonists: ACEA-1011 ATPO Becampanel Caroverine CNQX Dasolampanel DNQX Fanapanel (MPQX) GAMS Kaitocephalin Kynurenic acid Kynurenine Licostinel (ACEA-1021) NBQX PNQX Selurampanel Tezampanel Theanine Topiramate YM90K Zonampanel; Negative allosteric modulators: Barbiturates (e.g., pentobarbital, sodium thiopental) Cyclopropane Enflurane Ethanol (alcohol) Evans blue GYKI-52466 GYKI-53655 Halothane Irampanel Isoflurane Perampanel Pregnenolone sulfate Sevoflurane Talampanel; Unknown/unsorted antagonists: Minocycline KAR Agonists: Main site agonists: 5-Bromowillardiine 5-Iodowillardiine Acromelic acid (acromelate) AMPA ATPA Domoic acid Glutamate Ibotenic acid Kainic acid LY-339434 Proline Quisqualic acid SYM-2081; Positive allosteric modulators: Cyclothiazide Diazoxide Enflurane Halothane Isoflurane Antagonists: ACEA-1011 CNQX Dasolampanel DNQX GAMS Kaitocephalin Kynurenic acid Licostinel (ACEA-1021) LY-382884 NBQX NS102 Selurampanel Tezampanel Theanine Topiramate UBP-302; Negative allosteric modulators: Barbiturates (e.g., pentobarbital, sodium thiopental) Enflurane Ethanol (alcohol) Evans blue NS-3763 Pregnenolone sulfate NMDAR Agonists: Main site agonists: AMAA Aspartate Glutamate Homocysteic acid (L-HCA) Homoquinolinic acid Ibotenic acid NMDA Proline Quinolinic acid Tetrazolylglycine Theanine; Glycine site agonists: β-Fluoro-D-alanine ACBD ACC (ACPC) ACPD AK-51 Apimostinel (NRX-1074) B6B21 CCG D-Alanine D-Cycloserine D-Serine DHPG Dimethylglycine Glycine HA-966 L-687414 L-Alanine L-Serine Milacemide Neboglamine (nebostinel) Rapastinel (GLYX-13) Sarcosine; Polyamine site agonists: Neomycin Spermidine Spermine; Other positive allosteric modulators: 24S-Hydroxycholesterol DHEA (prasterone) DHEA sulfate (prasterone sulfate) Epipregnanolone sulfate Pregnenolone sulfate SAGE-201 SAGE-301 SAGE-718 Antagonists: Competitive antagonists: AP5 (APV) AP7 CGP-37849 CGP-39551 CGP-39653 CGP-40116 CGS-19755 CPP Kaitocephalin LY-233053 LY-235959 LY-274614 MDL-100453 Midafotel (d-CPPene) NPC-12626 NPC-17742 PBPD PEAQX Perzinfotel PPDA SDZ-220581 Selfotel; Glycine site antagonists: 4-Cl-KYN (AV-101) 5,7-DCKA 7-CKA ACC ACEA-1011 ACEA-1328 Apimostinel (NRX-1074) AV-101 Carisoprodol CGP-39653 CNQX D-Cycloserine DNQX Felbamate Gavestinel GV-196771 Harkoseride Kynurenic acid Kynurenine L-689560 L-701324 Licostinel (ACEA-1021) LU-73068 MDL-105519 Meprobamate MRZ 2/576 PNQX Rapastinel (GLYX-13) ZD-9379; Polyamine site antagonists: Arcaine Co 101676 Diaminopropane Diethylenetriamine Huperzine A Putrescine; Uncompetitive pore blockers (mostly dizocilpine site): 2-MDP 3-HO-PCP 3-MeO-PCE 3-MeO-PCMo 3-MeO-PCP 4-MeO-PCP 8A-PDHQ 18-MC α-Endopsychosin Alaproclate Alazocine (SKF-10047) Amantadine Aptiganel Argiotoxin-636 Arketamine ARL-12495 ARL-15896-AR ARL-16247 Budipine Coronaridine Delucemine (NPS-1506) Dexoxadrol Dextrallorphan Dextromethadone Dextromethorphan Dextrorphan Dieticyclidine Diphenidine Dizocilpine Ephenidine Esketamine Etoxadrol Eticyclidine Fluorolintane Gacyclidine Ibogaine Ibogamine Indantadol Ketamine Ketobemidone Lanicemine Levomethadone Levomethorphan Levomilnacipran Levorphanol Loperamide Memantine Methadone Methorphan Methoxetamine Methoxphenidine Milnacipran Morphanol NEFA Neramexane Nitromemantine Noribogaine Norketamine Orphenadrine PCPr PD-137889 Pethidine (meperidine) Phencyclamine Phencyclidine Propoxyphene Remacemide Rhynchophylline Rimantadine Rolicyclidine Sabeluzole Tabernanthine Tenocyclidine Tiletamine Tramadol; Ifenprodil (NR2B) site antagonists: Besonprodil Buphenine (nylidrin) CO-101244 (PD-174494) Eliprodil Haloperidol Isoxsuprine Radiprodil (RGH-896) Rislenemdaz (CERC-301, MK-0657) Ro 8-4304 Ro 25-6981 Safaprodil Traxoprodil (CP-101606); NR2A-selective antagonists: MPX-004 MPX-007 TCN-201 TCN-213; Cations: Hydrogen Magnesium Zinc; Alcohols/volatile anesthetics/related: Benzene Butane Chloroform Cyclopropane Desflurane Diethyl ether Enflurane Ethanol (alcohol) Halothane Hexanol Isoflurane Methoxyflurane Nitrous oxide Octanol Sevoflurane Toluene Trichloroethane Trichloroethanol Trichloroethylene Urethane Xenon Xylene; Unknown/unsorted antagonists: ARR-15896 Bumetanide Caroverine Conantokin D-αAA Dexanabinol Flufenamic acid Flupirtine FPL-12495 FR-115427 Furosemide Hodgkinsine Ipenoxazone (MLV-6976) MDL-27266 Metaphit Minocycline MPEP Niflumic acid Pentamidine Pentamidine isethionate Piretanide Psychotridine Transcrocetin (saffron) Unsorted: Allosteric modulators: AGN-241751 See also: Receptor/signaling modulators Metabotropic glutamate receptor modulators Glutamate metabolism/transport modulators v t e Nicotinic acetylcholine receptor modulators nAChRs Agonists (and PAMs) 5-HIAA A-84,543 A-366,833 A-582,941 A-867,744 ABT-202 ABT-418 ABT-560 ABT-894 Acetylcholine Altinicline Anabasine Anatoxin-a AR-R17779 Bephenium hydroxynaphthoate Butinoline Butyrylcholine Carbachol Choline Cotinine Cytisine Decamethonium Desformylflustrabromine Dianicline Dimethylphenylpiperazinium Epibatidine Epiboxidine Ethanol (alcohol) Ethoxysebacylcholine EVP-4473 EVP-6124 Galantamine GTS-21 Ispronicline Ivermectin JNJ-39393406 Levamisole Lobeline MEM-63,908 (RG-3487) Morantel Nicotine (tobacco) NS-1738 PHA-543,613 PHA-709,829 PNU-120,596 PNU-282,987 Pozanicline Pyrantel Rivanicline RJR-2429 Sazetidine A SB-206553 Sebacylcholine SIB-1508Y SIB-1553A SSR-180,711 Suberyldicholine Suxamethonium (succinylcholine) Suxethonium (succinyldicholine) TC-1698 TC-1734 TC-1827 TC-2216 TC-5214 TC-5619 TC-6683 Tebanicline Tribendimidine Tropisetron UB-165 Varenicline WAY-317,538 XY-4083 Antagonists (and NAMs) 18-MAC 18-MC α-Neurotoxins (e.g., α-bungarotoxin, α-cobratoxin, α-conotoxin, many others) ABT-126 Alcuronium Allopregnanolone Amantadine Anatruxonium AQW051 Atracurium Barbiturates (e.g., pentobarbital, sodium thiopental) BNC-210 Bungarotoxins (e.g., α-bungarotoxin, κ-bungarotoxin) Bupropion BW-A444 Candocuronium iodide (chandonium iodide) Chlorisondamine Cisatracurium Coclaurine Coronaridine Curare Cyclopropane Dacuronium bromide Decamethonium Dehydronorketamine Desflurane Dextromethorphan Dextropropoxyphene Dextrorphan Diadonium DHβE Dihydrochandonium Dimethyltubocurarine (metocurine) Dioscorine Dipyrandium Dizocilpine (MK-801) Doxacurium Encenicline Enflurane Erythravine Esketamine Fazadinium Gallamine Gantacurium chloride Halothane Hexafluronium Hexamethonium (benzohexonium) Hydroxybupropion Hydroxynorketamine Ibogaine Isoflurane Ketamine Kynurenic acid Laudanosine Laudexium (laudolissin) Levacetylmethadol Levomethadone Malouetine ME-18-MC Mecamylamine Memantine Methadone Methorphan (racemethorphan) Methyllycaconitine Metocurine Mivacurium Morphanol (racemorphan) Neramexane Nitrous oxide Norketamine Pancuronium bromide Pempidine Pentamine Pentolinium Phencyclidine Pipecuronium bromide Progesterone Promegestone Radafaxine Rapacuronium bromide Reboxetine Rocuronium bromide Sevoflurane Stercuronium iodide Surugatoxin Thiocolchicoside Toxiferine Tramadol Trimetaphan camsilate (trimethaphan camsylate) Tropeinium Tubocurarine Vanoxerine Vecuronium bromide Xenon Precursors (and prodrugs) Acetyl-coA Adafenoxate Choline (lecithin) Citicoline Cyprodenate Dimethylethanolamine Glycerophosphocholine Meclofenoxate (centrophenoxine) Phosphatidylcholine Phosphatidylethanolamine Phosphorylcholine Pirisudanol See also: Receptor/signaling modulators • Muscarinic acetylcholine receptor modulators • Acetylcholine metabolism/transport modulators

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