Biology:GABAA receptor negative allosteric modulator

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Short description: Drug class


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 also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "GABA(A) receptor channel pharmacology". Curr. Pharm. Des. 11 (15): 1867–85. 2005. doi:10.2174/1381612054021024. PMID 15974965. 
  2. ↑ 2.0 2.1 2.2 2.3 Harry Majewski (29 October 2009). Pharmacology - Volume I. EOLSS Publications. pp. 58–. ISBN 978-1-84826-180-8. https://books.google.com/books?id=CCNVCwAAQBAJ&pg=PA58. 
  3. ↑ 3.0 3.1 "Flumazenil: a benzodiazepine antagonist". Clin Pharm 12 (9): 641–56; quiz 699–701. September 1993. PMID 8306565. 
  4. ↑ 4.0 4.1 "Flumazenil: a new benzodiazepine antagonist". Ann Emerg Med 20 (2): 181–8. February 1991. doi:10.1016/s0196-0644(05)81219-3. PMID 1996802. 
  5. ↑ "Flumazenil and seizures: analysis of 43 cases". Clin Ther 14 (2): 292–305. 1992. PMID 1611650. 
  6. ↑ "Flumazenil--treatment or toxin". J. Toxicol. Clin. Toxicol. 42 (2): 209–16. 2004. doi:10.1081/clt-120030946. PMID 15214628. 
  7. ↑ "The physiological properties and therapeutic potential of alpha5-GABAA receptors". Biochem. Soc. Trans. 37 (Pt 6): 1334–7. December 2009. doi:10.1042/BST0371334. PMID 19909271. 
  8. ↑ 8.0 8.1 "Selective Modulators of α5-Containing GABAA Receptors and their Therapeutic Significance". Curr Drug Targets 16 (7): 735–46. 2015. doi:10.2174/1389450116666150309120235. PMID 25751008. https://espace.library.uq.edu.au/view/UQ:368241/UQ368241_OA.pdf. 
  9. ↑ 9.0 9.1 "GABAA receptor subtypes: Therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism". Annu. Rev. Pharmacol. Toxicol. 54: 483–507. 2014. doi:10.1146/annurev-pharmtox-011613-135947. PMID 24160694. 
  10. ↑ 10.0 10.1 "The role of α5 GABAA receptor agonists in the treatment of cognitive deficits in schizophrenia". Curr. Pharm. Des. 20 (31): 5069–76. 2014. doi:10.2174/1381612819666131216114612. PMID 24345268. 
  11. ↑ "Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide". F1000Res 7: 659. 2018. doi:10.12688/f1000research.14344.1. PMID 29899972. 
  12. ↑ "Convergent Mechanisms Underlying Rapid Antidepressant Action". CNS Drugs 32 (3): 197–227. March 2018. doi:10.1007/s40263-018-0492-x. PMID 29516301. 
  13. ↑ "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. October 2015. doi:10.1038/npp.2015.112. PMID 25900119. 
  14. ↑ 14.0 14.1 Norman Delanty (27 November 2001). Seizures: Medical Causes and Management. Springer Science & Business Media. pp. 203–. ISBN 978-1-59259-094-0. https://books.google.com/books?id=Nh2sBAAAQBAJ&pg=PT203. 
  15. ↑ "Cephalosporin antibiotics are weak blockers of GABAa receptor-mediated synaptic transmission in rat brain slices". Biochem. Biophys. Res. Commun. 499 (4): 868–874. May 2018. doi:10.1016/j.bbrc.2018.04.008. PMID 29625107. 
  16. ↑ "Drug safety is a barrier to the discovery and development of new androgen receptor antagonists". Prostate 71 (5): 480–8. April 2011. 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. 


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See also
Receptor/signaling modulators
GABAA receptor positive modulators
GABA metabolism/transport modulators

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