GABAA Receptor Modulators


Allosteric modulators are molecules that act at sites different from orthosteric sites and influence the effects of orthosteric ligands on the target protein. For the family of GABAA receptors, allosteric modulation is a key concept exploited by widely used pharmaceuticals, for example tranquilisers of the benzodiazepine type or sedative anaesthetics such as etomidate. Recent developments reflect efforts to identify the binding sites involved in such allosteric modulation and the selective targeting of individual receptor subtypes. The precise number and structures of native GABAA receptor subtypes are still not known. A widely used useful distinction refers to synaptic and extrasynaptic pools of receptors, and some progress has been made in targeting these pools separately. A recent surge identified endogenous modulators, among them endocannabinoids and dopamine. As knowledge about modulators as well as their binding sites increases, development of more selective agents will be facilitated.

Key Concepts

  • Clinically used drugs targeting GABAA receptors are mostly allosteric modulators – benzodiazepines and sedative narcotics are prominent examples.
  • Allosteric modulators change agonist function in various ways by interactions with allosteric modulatory sites.
  • Diverse effects have been categorised; acronyms such as PAM type I and similar are used – but the terminology is not standardised.
  • Functional selectivity has been introduced as a term to differentiate selective action from selective binding.
  • For many chemotypes the exact binding sites on GABAA receptors are not yet known; structural knowledge is still needed.
  • While receptors consisting of alpha, beta and gamma subunits are very well characterised, much less is known about receptors that contain only alpha and beta subunits and receptors that contain delta, pi, theta, epsilon or rho subunits.

Keywords: GABAA receptor; subtype; allosteric modulation; PAM; SAM; NAM

Figure 1. (a) Schematic rendering of a benzodiazepine‐sensitive αβγ‐receptor subtype, known extracellular binding sites indicated. Additional schemes depict representative putative composition and arrangements of αβ‐ and αβδ‐receptor subtypes. (b) The ribbon structure depicts 6HUP (Masiulis et al., ) from the perspective indicated by the arrow in panel a. The two subunits in the back are very light grey, the beta subunit on the left‐hand side is black, the alpha subunit in front in dark grey and the gamma subunit in light grey. In the ECD, GABA is present at the orthosteric site. The ‘etomidate’ site at the upper TMD β+/α− interface was found to be occupied by diazepam, in line with previous mutational analysis (Walters et al., ). The high‐affinity benzodiazepine‐binding site is also occupied by diazepam and revealed the binding mode of diazepam, which is different from the one seen for flumazenil (Zhu et al., ).
Figure 2. The range of allosteric modulation elicited by the high‐affinity benzodiazepine‐binding site (of α1βγ2 receptors) can be conceived as full negative modulation (thus reducing GABA‐elicited currents strongly), no change and full positive modulation. In the case of these compounds, the maximum enhancement would be the current elicited by saturating GABA concentrations – however, in receptors for which GABA is a partial agonist, modulators can enhance the current above GABAmax.
Figure 3. Updated scheme of allosteric sites on GABAA receptor subtypes. (a) A highly schematic rendering of known ECD‐ and TMD‐binding sites in a canonical αβγ‐receptor subtype: The canonical GABA sites, the high‐affinity benzodiazepine (Bz) site, a modulatory sites used by pyrazoloquinolinones (PQ), etomidate/loreclezole sites (Eto), barbiturate sites (B), the interface neurosteroid site (S) and the site for the negative modulatory steroid pregnanolone sulfate (S‐). Additional putative sites are indicated in line with recent structural evidence. (b) A side view of a generic pentameric complex, with the same binding sites arranged along the front interface. The scheme rests largely on structural evidence, but the ICD is only indicative of the fact that it is highly variable and thus will differ considerably among subunit classes. 1, 1a: ECD interface sites (GABA, benzodiazepine and PQ), can be occupied by one ligand or several ligands simultaneously; 2: cation‐binding site; 3: etomidate/loreclezole/barbiturate/low‐affinity benzodiazepine site; 4: modulatory steroid site; 5, 6, 7: tentative sites seen in other pLGICs; 8: lipid‐associated site used by inhibitory steroids and endocannabinoids; 9: lipid/cholesterol interaction site, tentative modulatory site.
Figure 4. A selection of molecules to depict the wide variety of different chemical scaffolds that act on the GABAA‐receptor family. The selection is meant to illustrate the big chemical diversity of modulators with some clinically relevant examples (zolpidem, allopregnanolone and thiopental) and some additional examples such as the small ethanol molecule, more complex isoprene structures such as valerenic acid, a representative nonsteroid endogenous modulator (histamine), the (functionally) delta‐selective compound DS2 and examples for polyspecific compounds with less‐discussed ‘off target’ effects at GABAA receptors such as the synthetic narcotic ketamine and the drug of abuse cocaine (Hondebrink et al., ).


Antkowiak B and Rammes G (2019) GABA(A) receptor‐targeted drug development – New perspectives in perioperative anesthesia. Expert Opinion on Drug Discovery 14 (7): 683–699. DOI: 10.1080/17460441.2019.1599356.

Bakas T, van Nieuwenhuijzen PS, Devenish SO, et al. (2017) The direct actions of cannabidiol and 2‐arachidonyl glycerol at GABAA receptors. Pharmacological Research 119: 358–370. DOI: 10.1016/j.phrs.2017.02.022.

Bennett BD, Huguenard JR and Prince DA (1998) Adrenergic modulation of GABAA receptor‐mediated inhibition in rat sensorimotor cortex. Journal of Neurophysiology 79 (2): 937–946. DOI: 10.1152/jn.1998.79.2.937.

Bertrand D and Gopalakrishnan M (2007) Allosteric modulation of nicotinic acetylcholine receptors. Biochemical Pharmacology 74 (8): 1155–1163. DOI: 10.1016/j.bcp.2007.07.011.

Blouin RT, Seifert HA, Babenco HD, Conard PF and Gross JB et al. (1993) Propofol depresses the hypoxic ventilatory response during conscious sedation and isohypercapnia. Anesthesiology 79 (6): 1177–1182.

Brejc K, van Dijk WJ, Klaassen RV, et al. (2001) Crystal structure of an ACh‐binding protein reveals the ligand‐binding domain of nicotinic receptors. Nature 411 (6835): 269–276. DOI: 10.1038/35077011.

Brickley SG and Mody I (2012) Extrasynaptic GABA(A) receptors: their function in the CNS and implications for disease. Neuron 73 (1): 23–34. DOI: 10.1016/j.neuron.2011.12.012.

Chen Q, Wells MM, Arjunan P, et al. (2018) Structural basis of neurosteroid anesthetic action on GABAA receptors. Nature Communications 9 (1): 3972. DOI: 10.1038/s41467‐018‐06361‐4.

Chen Z‐W, Bracamontes JR, Budelier MM, et al. (2019) Multiple functional neurosteroid binding sites on GABAA receptors. PLoS Biology 17 (3): e3000157. DOI: 10.1371/journal.pbio.3000157.

Çiçek SS (2018) Structure‐dependent activity of natural GABA(A) receptor modulators. Molecules (Basel, Switzerland) 23 (7). DOI: 10.3390/molecules23071512.

Crestani F and Rudolph U (2015) Behavioral functions of GABAA receptor subtypes – the Zurich experience. Advances in Pharmacology (San Diego, Calif.) 72: 37–51. DOI: 10.1016/bs.apha.2014.10.001.

Donoghue J and Lader M (2010) Usage of benzodiazepines: a review. International Journal of Psychiatry in Clinical Practice 14 (2): 78–87. DOI: 10.3109/13651500903447810.

Dündar Y, Boland A, Strobl J, et al. (2004) Newer hypnotic drugs for the short‐term management of insomnia: a systematic review and economic evaluation. Health Technology Assessment (Winchester) 8 (24): iii–x, 1–125. .

Ebert TJ (2005) Sympathetic and hemodynamic effects of moderate and deep sedation with propofol in humans. Anesthesiology 103 (1): 20–24. DOI: 10.1097/00000542‐200507000‐00007.

Feng AY, Kaye AD, Kaye RJ, Belani K and Urman RD (2017) Novel propofol derivatives and implications for anesthesia practice. Journal of Anaesthesiology Clinical Pharmacology 33 (1): 9. DOI: 10.4103/0970‐9185.202205.

Fleck MW, Thomson JL and Hough LB (2012) Histamine‐gated ion channels in mammals? Biochemical Pharmacology 83 (9): 1127–1135. DOI: 10.1016/j.bcp.2011.12.011.

Gee KW, Tran MB, Hogenkamp DJ, et al. (2010) Limiting activity at β1‐subunit‐containing GABAA receptor subtypes reduces ataxia. Journal of Pharmacology and Experimental Therapeutics 332 (3): 1040–1053. DOI: 10.1124/jpet.109.161885.

Glauser T, Shinnar S, Gloss D, et al. (2016) Evidence‐based guideline: treatment of convulsive status epilepticus in children and adults: report of the Guideline Committee of the American Epilepsy Society. Epilepsy Currents 16 (1): 48–61. DOI: 10.5698/1535‐7597‐16.1.48.

Hanrahan JR, Chebib M and Johnston GA (2011) Flavonoid modulation of GABAA receptors. British Journal of Pharmacology 163 (2): 234–245. DOI: 10.1111/j.1476‐5381.2011.01228.x.

Hoerbelt P, Lindsley TA and Fleck MW (2015) Dopamine directly modulates GABAA receptors. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 35 (8): 3525–3536. DOI: 10.1523/JNEUROSCI.4390‐14.2015.

Hondebrink L, Tan S, Hermans E, et al. (2013) Additive inhibition of human α 1 β 2 γ 2 GABA A receptors by mixtures of commonly used drugs of abuse. Neurotoxicology 35 (1): 23–29. DOI: 10.1016/j.neuro.2012.12.003.

Hu Z, Oh S, Ha TW, Hong JT and Oh KW (2018) Sleep‐aids derived from natural products. Biomolecules & Therapeutics 26 (4): 343–349. DOI: 10.4062/biomolther.2018.099.

Johnston GA, Hanrahan JR, Chebib M, Duke RK and Mewett KN (2006) Modulation of ionotropic GABA receptors by natural products of plant origin. Advances in Pharmacology 54: 285–316. DOI: 10.1016/S1054‐3589(06)54012‐8.

Klinger F, Bajric M, Salzer I, et al. (2015) δ Subunit‐containing GABAA receptors are preferred targets for the centrally acting analgesic flupirtine. British Journal of Pharmacology 172 (20): 4946–4958. DOI: 10.1111/bph.13262.

Kudryavtsev DS, Shelukhina IV, Son LV, et al. (2015) Neurotoxins from snake venoms and α‐conotoxin ImI inhibit functionally active ionotropic γ‐aminobutyric acid (GABA) receptors. The Journal of Biological Chemistry 290 (37): 22747–22758. DOI: 10.1074/jbc.M115.648824.

Kumar M, González LA and Dillon GH (2015) Assessment of subunit‐dependent direct gating and allosteric modulatory effects of carisoprodol at GABA(A) receptors. Neuropharmacology 97: 414–425. DOI: 10.1016/j.neuropharm.2015.04.007.

Laverty D, Thomas P, Field M, et al. (2017) Crystal structures of a GABAA‐receptor chimera reveal new endogenous neurosteroid‐binding sites. Nature Structural & Molecular Biology 24 (11): 977–985. DOI: 10.1038/nsmb.3477.

Lee HJ, Absalom NL, Hanrahan JR, et al. (2016) A pharmacological characterization of GABA, THIP and DS2 at binary α4β3 and β3δ receptors: GABA activates β3δ receptors via the β3(+)δ(‐) interface. Brain Research. DOI: 10.1016/j.brainres.2016.05.019.

Malapero RJ, Zaccagnino MP, Brovman EY, Kaye AD and Urman RD (2017) Etomidate derivatives: novel pharmaceutical agents in anesthesia. Journal of Anaesthesiology Clinical Pharmacology 33 (4): 429–431. DOI: 10.4103/0970‐9185.222521.

Masiulis S, Desai R, Uchański T, et al. (2019) GABAA receptor signalling mechanisms revealed by structural pharmacology. Nature 565 (7740): 454–459. DOI: 10.1038/s41586‐018‐0832‐5.

Newcombe J, Chatzidaki A, Sheppard TD, Topf M and Millar NS (2018) Diversity of nicotinic acetylcholine receptor positive allosteric modulators revealed by mutagenesis and a revised structural model. Molecular Pharmacology 93 (2): 128–140. DOI: 10.1124/mol.117.110551.

Ochoa‐De La Paz LD, Estrada‐Mondragón A, Limón A, Miledi R and Martínez‐Torres A (2012) Dopamine and serotonin modulate human GABAρ1 receptors expressed in Xenopus laevis oocytes. ACS Chemical Neuroscience 3 (2): 96–104. DOI: 10.1021/cn200083m.

Phulera S, Zhu H, Yu J, et al. (2018) Cryo‐EM structure of the benzodiazepine‐sensitive α1β1γ2S tri‐heteromeric GABAA receptor in complex with GABA. eLife 7. DOI: 10.7554/eLife.39383.

Puthenkalam R, Hieckel M, Simeone X, et al. (2016) Structural studies of GABAA receptor binding sites: which experimental structure tells us what? Frontiers in Molecular Neuroscience 9 (JUNE). DOI: 10.3389/fnmol.2016.00044.

Rudolph U and Knoflach F (2011) Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nature Reviews. Drug Discovery 10 (9): 685–697. DOI: 10.1038/nrd3502.

Rudolph U and Möhler H (2014) GABA a receptor subtypes: therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism. Annual Review of Pharmacology and Toxicology 54 (1): 483–507. DOI: 10.1146/annurev‐pharmtox‐011613‐135947.

Sahinovic MM, Struys MMRF and Absalom AR (2018) Clinical pharmacokinetics and pharmacodynamics of propofol. Clinical Pharmacokinetics 57 (12): 1539–1558. DOI: 10.1007/s40262‐018‐0672‐3.

Sheriff F and Hinson H (2015) Pathophysiology and clinical management of moderate and severe traumatic brain injury in the ICU. Seminars in Neurology 35 (01): 042–049. DOI: 10.1055/s‐0035‐1544238.

Sieghart W (2015) Allosteric modulation of GABAA receptors via multiple drug‐binding sites. In: Advances in pharmacology (San Diego, Calif.), pp 53–96. DOI: 10.1016/bs.apha.2014.10.002.

Sieghart W and Savić MM (2018) International union of basic and clinical pharmacology. CVI: GABAA receptor subtype‐ and function‐selective ligands: key issues in translation to humans. Pharmacological Reviews 70 (4): 836–878. DOI: 10.1124/pr.117.014449.

Sigel E and Ernst M (2018) The benzodiazepine binding sites of GABAA receptors. Trends in Pharmacological Sciences 39 (7): 659–671. DOI: 10.1016/

Simeone X, Siebert DC, Bampali K, et al. (2017) Molecular tools for GABAA receptors: high affinity ligands for β1‐containing subtypes. Scientific Reports 7 (1): 5674. DOI: 10.1038/s41598‐017‐05757‐4.

Skerritt JH and Johnston GAR (1983) Enhancement of GABA binding by benzodiazepines and related anxiolytics. European Journal of Pharmacology 89 (3–4): 193–198. DOI: 10.1016/0014‐2999(83)90494‐6.

Spence J, Belley‐Côté E, Devereaux PJ, et al. (2018) Benzodiazepine administration during adult cardiac surgery: a survey of current practice among Canadian anesthesiologists working in academic centres. Canadian Journal of Anesthesia/Journal canadien d'anesthésie 65 (3): 263–271. DOI: 10.1007/s12630‐017‐1047‐1.

Swann A, Williams J and Fatovich DM (2007) Recall after procedural sedation in the emergency department. Emergency Medicine Journal : EMJ 24 (5): 322–324. DOI: 10.1136/emj.2006.040923.

Tonon MC, Vaudry H, Chuquet J, et al. (2019) Endozepines and their receptors: structure, functions and pathophysiological significance. Pharmacology & Therapeutics. DOI: 10.1016/j.pharmthera.2019.06.008.

Tretter V, Ehya N, Fuchs K and Sieghart W (1997) Stoichiometry and assembly of a recombinant GABA(A) receptor subtype. Journal of Neuroscience 17 (8): 2728–2737. DOI: 10.1523/jneurosci.17‐08‐02728.1997.

Treven M, Koenig X, Assadpour E, et al. (2015) The anticonvulsant retigabine is a subtype selective modulator of GABA A receptors. Epilepsia 56 (4): 647–657. DOI: 10.1111/epi.12950.

Yakoub K, Jung S, Sattler C, et al. (2018) Structure‐function evaluation of imidazopyridine derivatives selective for δ‐subunit‐containing γ‐aminobutyric acid type A (GABAA) receptors. Journal of Medicinal Chemistry 61 (5): 1951–1968. DOI: 10.1021/acs.jmedchem.7b01484.

Walters RJ, Hadley SH, Morris KD and Amin J (2000) Benzodiazepines act on GABAA receptors via two distinct and separable mechanisms. Nature Neuroscience 3 (12): 1274–1281. DOI: 10.1038/81800.

Zheleznova N, Sedelnikova A and Weiss DS (2008) α 1β 2δ, a silent GABA A receptor: Recruitment by tracazolate and neurosteroids. British Journal of Pharmacology 153 (5): 1062–1071. DOI: 10.1038/sj.bjp.0707665.

Zhu S, Noviello CM, Teng J, et al. (2018) Structure of a human synaptic GABAA receptor. Nature 559 (7712): 67–88. DOI: 10.1038/s41586‐018‐0255‐3.

Further Reading

Blanco M‐J, La D, Coughlin Q, et al. (2018) Breakthroughs in neuroactive steroid drug discovery. Bioorganic & Medicinal Chemistry Letters 28 (2): 61–70. DOI: 10.1016/j.bmcl.2017.11.043.

Patel B, Bright DP, Mortensen M, Frolund B and Smart TG (2016) Context‐dependent modulation of GABAAR‐mediated tonic currents. Journal of Neuroscience 36 (2): 607–621. DOI: 10.1523/JNEUROSCI.2047‐15.2016.

Solomon VR, Tallapragada VJ, Chebib M, Johnston GAR and Hanrahan JR (2019) GABA allosteric modulators: an overview of recent developments in non‐benzodiazepine modulators. European Journal of Medicinal Chemistry 171: 434–461. DOI: 10.1016/j.ejmech.2019.03.043.

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Ernst, Margot, Silva, Luca L, and Vogel, Florian D(May 2020) GABAA Receptor Modulators. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0028882]