A<unk>  is a<unk>  allosteric modulator (NAM), or inhibitor, of the<unk><unk> , a ligand-gated ion channel of the major inhibitory neurotransmitter γ-aminobutyric acid <unk> . They are closely related and similar to<unk><unk>  antagonists. The effects of<unk><unk>  NAMs are functionally the opposite of those of<unk><unk>  positive allosteric modulators (PAMs) like the benzodiazepines, barbiturates, and ethanol (alcohol). Non-selective<unk><unk>  NAMs can produce a variety of effects including convulsions, neurotoxicity, and anxiety, among others. Flumazenil is a competitive antagonist of the benzodiazepine site of the<unk><unk>  and hence is a<unk><unk>  NAM of sorts. It is used to reverse benzodiazepine overdose. The drug can provoke seizures in those with benzodiazepine dependence. Selective NAMs (or "inverse agonists") of α5 subunit-containing<unk><unk> s, such as basmisanil and α5IA, do not have convulsant or anxiogenic effects but instead show cognitive- and memory-enhancing or nootropic-like effects. They are under investigation for the treatment of cognitive impairment in conditions like Down syndrome and schizophrenia. In addition, the selective α5 subunit-containing<unk><unk>  NAMs L-655,708 and MRK-016 have been found to produce rapid-acting antidepressant effects in animals similar to those of the NMDA<unk>  antagonist ketamine, and are of interest for the potential treatment of depression. Additional selective α5 subunit-containing<unk><unk>  NAMs include PWZ-029, Ro4938581, and TB-21007. Certain drugs show weak<unk><unk>  NAM activity as an off-target activity that is responsible for undesirable side effects like anxiety, insomnia, and seizures. Examples include fluoroquinolone antibiotics like ciprofloxacin, β-lactam antibiotics like penicillin, ceftriaxone, and imipenem, nonsteroidal antiandrogens like enzalutamide and apalutamide, and the antidepressant bupropion. Other<unk>  NAMs, mostly non-selective, include amentoflavone, bemegride, bilobalide, cicutoxin, dieldrin, FG-7142, fipronil, flurothyl, iomazenil, laudanosine, lindane, oenanthotoxin, pentylenetetrazol, phenylsilatrane, picrotoxin, radequinil, Ro15-4513, sarmazenil, suritozole, terbequinil, tetramethylenedisulfotetramine (TETS), and ZK-93426 as well as the endogenous neurosteroids dehydroepiandrosterone sulfate (DHEA-S), pregnenolone sulfate, epipregnanolone, and isopregnanolone. Some naturally occurring<unk><unk>  NAMs like cicutoxin and picrotoxin are considered to be toxins, while other<unk><unk>  NAMs like dieldrin, fipronil, and TETS are used as pesticides (e.g., insecticides, rodenticides), and yet other<unk><unk>  NAMs like bemegride, flurothyl, and pentylenetetrazol are used for clinical purposes.
GABAA receptor negative allosteric modulator
GABAA receptor positive allosteric modulator
Norepinephrine–dopamine disinhibitor
Adenosine receptor antagonist
NMDA receptor antagonist
Chloride channel opener
Serotonin receptor agonist
GABA analogue