GABAA receptor negative allosteric modulator

A GABAA receptor negative allosteric modulator is a negative allosteric modulator (NAM), or inhibitor, of the GABAA receptor, a ligand-gated ion channel of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA).[1][2] They are closely related and similar to GABAA receptor antagonists.[1][2] The effects of GABAA receptor NAMs are functionally the opposite of those of GABAA receptor positive allosteric modulators (PAMs) like the benzodiazepines, barbiturates, and ethanol (alcohol).[1][2] Non-selective GABAA receptor NAMs can produce a variety of effects including convulsions, neurotoxicity, and anxiety, among others.[1][2]

Flumazenil is a competitive antagonist of the benzodiazepine site of the GABAA receptor and hence is a GABAA receptor NAM of sorts.[1][3][4] It is used to reverse benzodiazepine overdose.[3][4] The drug can provoke seizures in those with benzodiazepine dependence.[5][6]

Selective NAMs (or "inverse agonists") of α5 subunit-containing GABAA receptors, such as basmisanil and α5IA, do not have convulsant or anxiogenic effects but instead show cognitive- and memory-enhancing or nootropic-like effects.[7][8][9][10] They are under investigation for the treatment of cognitive impairment in conditions like Down syndrome and schizophrenia.[8][9][10] In addition, the selective α5 subunit-containing GABAA 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.[11][12][13] Additional selective α5 subunit-containing GABAA receptor NAMs include PWZ-029, Ro4938581, and TB-21007.

Certain drugs show weak GABAA 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,[14] β-lactam antibiotics like penicillin, ceftriaxone, and imipenem,[14][15] nonsteroidal antiandrogens like enzalutamide and apalutamide,[16] and the antidepressant bupropion.[17]

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

See alsoEdit


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  8. ^ a b Soh MS, Lynch JW (2015). "Selective Modulators of α5-Containing GABAA Receptors and their Therapeutic Significance" (PDF). Curr Drug Targets. 16 (7): 735–46. doi:10.2174/1389450116666150309120235. PMID 25751008.
  9. ^ a b Rudolph U, Möhler H (2014). "GABAA receptor subtypes: Therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism". Annu. Rev. Pharmacol. Toxicol. 54: 483–507. doi:10.1146/annurev-pharmtox-011613-135947. PMC 3997216. PMID 24160694.
  10. ^ a b Gill KM, Grace AA (2014). "The role of α5 GABAA receptor agonists in the treatment of cognitive deficits in schizophrenia". Curr. Pharm. Des. 20 (31): 5069–76. doi:10.2174/1381612819666131216114612. PMC 4074253. PMID 24345268.
  11. ^ Duman RS (2018). "Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide". F1000Res. 7: 659. doi:10.12688/f1000research.14344.1. PMC 5968361. PMID 29899972.
  12. ^ Zanos P, Thompson SM, Duman RS, Zarate CA, Gould TD (March 2018). "Convergent Mechanisms Underlying Rapid Antidepressant Action". CNS Drugs. 32 (3): 197–227. doi:10.1007/s40263-018-0492-x. PMC 6005380. PMID 29516301.
  13. ^ Fischell J, Van Dyke AM, Kvarta MD, LeGates TA, Thompson SM (October 2015). "Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5-Containing GABAA Receptors". Neuropsychopharmacology. 40 (11): 2499–509. doi:10.1038/npp.2015.112. PMC 4569955. PMID 25900119.
  14. ^ a b Norman Delanty (27 November 2001). Seizures: Medical Causes and Management. Springer Science & Business Media. pp. 203–. ISBN 978-1-59259-094-0.
  15. ^ Amakhin DV, Soboleva EB, Zaitsev AV (May 2018). "Cephalosporin antibiotics are weak blockers of GABAa receptor-mediated synaptic transmission in rat brain slices". Biochem. Biophys. Res. Commun. 499 (4): 868–874. doi:10.1016/j.bbrc.2018.04.008. PMID 29625107.
  16. ^ Foster WR, Car BD, Shi H, Levesque PC, Obermeier MT, Gan J, Arezzo JC, Powlin SS, Dinchuk JE, Balog A, Salvati ME, Attar RM, Gottardis MM (April 2011). "Drug safety is a barrier to the discovery and development of new androgen receptor antagonists". Prostate. 71 (5): 480–8. doi:10.1002/pros.21263. PMID 20878947.
  17. ^ Thompson, Jeremy M.; Pappu, Aneesh; Pandhare, Akash; Jansen, Michaela (2015). "Complex Modulation of the GABAA α1β2γ2 Receptor Function by Bupropion". Biophysical Journal. 108 (2): 433a. doi:10.1016/j.bpj.2014.11.2366. ISSN 0006-3495.