GABAA Receptor Modulators

Abstract

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., ).
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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. http://www.els.net [doi: 10.1002/9780470015902.a0028882]