GABAA receptor negative allosteric modulator

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 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 benzodiazepines, barbiturates, and ethanol (alcohol).Non-selective GABA_A receptor 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 GABA_A receptor and hence is a GABA_A receptor 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 GABA_A receptors, 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 GABA_A receptor NAMs L-655,708 and MRK-016 have been found to produce rapid-acting antidepressant effects in animals similar to those of the NMDA receptor antagonist ketamine, and are of interest for the potential treatment of depression. Additional selective α₅ subunit-containing GABA_A receptor NAMs include PWZ-029, Ro4938581, and TB-21007.

Certain drugs show weak GABA_A receptor 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 GABA_A 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 GABA_A receptor NAMs like cicutoxin and picrotoxin are considered to be toxins, while other GABA_A receptor NAMs like dieldrin, fipronil, and TETS are used as pesticides (e.g., insecticides, rodenticides), and yet other GABA_A receptor NAMs like bemegride, flurothyl, and pentylenetetrazol are used for clinical purposes.

See also

• GABA_A receptor positive allosteric modulator
• AMPA receptor positive allosteric modulator
• List of investigational antidepressants