A GABA_A receptor negative allosteric modulator is a negative allosteric modulator (NAM), or inhibitor, of the GABA_A receptor, a ligand-gated ion channel of the major inhibitory

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neu ...

γ-aminobutyric acid (GABA). They are closely related and similar to GABA_A receptor antagonists. The effects of GABA_A receptor NAMs are functionally the opposite of those of GABA_A receptor positive allosteric modulators (PAMs) like the

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...

barbiturate Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential a ...

s, and

ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...

(

alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...

Non-selective In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mole ...

GABA_A receptor NAMs can produce a variety of effects including convulsions, neurotoxicity, and

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

, among others. Flumazenil is a

competitive antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rec ...

of the

site of the GABA_A receptor and hence is a GABA_A receptor NAM of sorts. It is used to reverse

benzodiazepine overdose Benzodiazepine overdose describes the ingestion of one of the drugs in the benzodiazepine class in quantities greater than are recommended or generally practiced. The most common symptoms of overdose include central nervous system (CNS) depressio ...

. The drug can provoke

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with lo ...

s in those with

benzodiazepine dependence Benzodiazepine dependence defines a situation in which one has developed one or more of either tolerance, withdrawal symptoms, drug seeking behaviors, such as continued use despite harmful effects, and maladaptive pattern of substance use, accord ...

. Selective NAMs (or "

inverse agonist In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. A neutral antagonist has no activity in the absence of an agonist or inverse ago ...

s") of α₅ subunit-containing GABA_A receptors, such as

basmisanil Basmisanil (; developmental codes RG-1662 and RO5186582) is a highly selective inverse agonist/negative allosteric modulator of α5 subunit-containing GABAA receptors which is under development by Roche for the treatment of cognitive impairmen ...

and α₅IA, do not have convulsant or anxiogenic effects but instead show

cognitive Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought ...

- and

memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remember ...

-enhancing or nootropic-like effects. They are under investigation for the treatment of cognitive impairment in conditions like

Down syndrome Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual d ...

and

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...

. In addition, the selective α₅ subunit-containing GABA_A receptor NAMs

L-655,708 L-655,708 (FG-8094) is a nootropic drug invented in 1996 by a team working for Merck, Sharp and Dohme, that was the first compound developed which acts as a subtype-selective inverse agonist at the α5 subtype of the benzodiazepine binding site ...

and

MRK-016 MRK-016 is a selective α5 subunit-containing GABAA negative allosteric modulator, that has nootropic properties. It has been found to produce rapid, ketamine-like antidepressant effects in animal model An animal model (short for animal disease ...

have been found to produce

rapid-acting antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, heada ...

effects in animals similar to those of the NMDA receptor antagonist

ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppress ...

, and are of interest for the potential treatment of depression. Additional selective α₅ subunit-containing GABA_A receptor NAMs include

PWZ-029 PWZ-029 is a benzodiazepine derivative drug with nootropic effects developed by WiSys,US Patent application US2006/258643 A1 It acts as a subtype-selective, mixed agonist-inverse agonist at the benzodiazepine binding site on the GABAA receptor, ...

Ro4938581 Ro4938581 is a nootropic drug invented in 2009 by a team working for Hoffmann-La Roche, which acts as a subtype-selective inverse agonist at the α5 subtype of the benzodiazepine binding site on the GABAA receptor. It has good selectivity for ...

, and

TB-21007 TB-21007 is a nootropic drug which acts as a subtype-selective inverse agonist at the α5 containing GABAA receptors Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces a ...

. Certain drugs show weak GABA_A receptor NAM activity as an off-target activity that is responsible for undesirable side effects like

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

, and

s. Examples include fluoroquinolone

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...

s like

ciprofloxacin Ciprofloxacin is a fluoroquinolone antibiotic used to treat a number of bacterial infections. This includes bone and joint infections, intra abdominal infections, certain types of infectious diarrhea, respiratory tract infections, skin i ...

, β-lactam antibiotics like

penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from '' Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum usin ...

ceftriaxone Ceftriaxone, sold under the brand name Rocephin, is a third-generation cephalosporin antibiotic used for the treatment of a number of bacterial infections. These include middle ear infections, endocarditis, meningitis, pneumonia, bone and join ...

, and imipenem, nonsteroidal antiandrogens like enzalutamide and

apalutamide Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is specifically indicated for use in conjunction with castration in the treatmen ...

, and the

antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common Side effect, side-effects of antidepressants include Xerostomia, dry mouth, weig ...

bupropion Bupropion, sold under the brand names Wellbutrin and Zyban among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. It is also popular as an add-on medication in the cas ...

. Other GABA_A NAMs, mostly non-selective, include amentoflavone,

bemegride Bemegride (trademarked as Megimide) is a central nervous system stimulant. The drug was first made in 1911. It has been used in hypnotic overdose. As with other chemoreceptor agonists, it is a potent emetic at doses above those normally used in ...

bilobalide Bilobalide is a biologically active terpenic tri lactone present in ''Ginkgo biloba''. Chemistry Bilobalide is a main constituent of the terpenoids found in Ginkgo leaves. It also exists in minor amounts in the roots. It is a sesquiterpenoid, i ...

cicutoxin Cicutoxin is a naturally-occurring poisonous chemical compound produced by several plants from the family Apiaceae including water hemlock (''Cicuta'' species) and water dropwort (''Oenanthe crocata''). The compound contains polyene, polyyne, ...

dieldrin Dieldrin is an organochloride originally produced in 1948 by J. Hyman & Co, Denver, as an insecticide. Dieldrin is closely related to aldrin, which reacts further to form dieldrin. Aldrin is not toxic to insects; it is oxidized in the insect to ...

, FG-7142,

fipronil Fipronil is a broad-spectrum insecticide that belongs to the phenylpyrazole chemical family. Fipronil disrupts the insect central nervous system by blocking the ligand-gated ion channel of the GABAA receptor and glutamate-gated chloride (GluC ...

, flurothyl, iomazenil,

laudanosine Laudanosine or ''N''-methyltetrahydropapaverine is a recognized metabolite of atracurium and cisatracurium. Laudanosine decreases the seizure threshold, and thus it can induce seizures if present at sufficient threshold concentrations; however suc ...

lindane Lindane, also known as ''gamma''-hexachlorocyclohexane (γ-HCH), gammaxene, Gammallin and benzene hexachloride (BHC), is an organochlorine chemical and an isomer of hexachlorocyclohexane that has been used both as an agricultural insecticide and ...

, oenanthotoxin, pentylenetetrazol, phenylsilatrane, picrotoxin, radequinil,

Ro15-4513 Ro15-4513 ''(IUPAC: Ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-1,4-benzodiazepine-3-carboxylate)'' is a weak partial inverse agonist of the benzodiazepine class of drugs, developed by Hoffmann–La Roche in the 1980s. It acts as a invers ...

, sarmazenil,

suritozole Suritozole (MDL 26,479) is an investigational cognition enhancer. It acts as a partial inverse agonist at the benzodiazepine receptor site on the GABAA ion channel complex, but does not have either anxiogenic or convulsant effects, unlike other B ...

, terbequinil, tetramethylenedisulfotetramine (TETS), and ZK-93426 as well as the

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, ...

neurosteroid Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term ''neurosteroid'' was co ...

s dehydroepiandrosterone sulfate (DHEA-S),

pregnenolone sulfate Pregnenolone sulfate (PS, PREGS) is an endogenous excitatory neurosteroid that is synthesized from pregnenolone. It is known to have cognitive and memory-enhancing, antidepressant, anxiogenic, and proconvulsant effects. Biological activity Pr ...

epipregnanolone Epipregnanolone, also known as 3β-hydroxy-5β-pregnan-20-one, 3β,5β-tetrahydroprogesterone, or 3β,5β-THP, is an endogenous neurosteroid. It acts as a negative allosteric modulator of the GABAA receptor and reverses the effects of potentiato ...

, and

isopregnanolone Isopregnanolone, also known as isoallopregnanolone and epiallopregnanolone, as well as sepranolone (), and as 3β-hydroxy-5α-pregnan-20-one or 3β,5α-tetrahydroprogesterone (3β,5α-THP), is an endogenous neurosteroid and a natural 3β-epimer of ...

. Some naturally occurring GABA_A receptor NAMs like cicutoxin and picrotoxin are considered to be

toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849 ...

s, while other GABA_A receptor NAMs like dieldrin, fipronil, and TETS are used as

pesticide Pesticides are substances that are meant to control pests. This includes herbicide, insecticide, nematicide, molluscicide, piscicide, avicide, rodenticide, bactericide, insect repellent, animal repellent, microbicide, fungicide, and ...

s (e.g.,

insecticide Insecticides are substances used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. Insecticides are used in agriculture, medicine, industry and by consumers. Insecticides are claimed t ...

s, rodenticides), and yet other GABA_A receptor NAMs like bemegride, flurothyl, and pentylenetetrazol are used for clinical purposes.

References

{{GABA receptor modulators Convulsants GABAA receptor negative allosteric modulators Pesticides

See also

References