Abstract
γ-Aminobutyric-acid type A (GABAA) receptors expressing the γ1 or γ3 subunit are only found within a few regions of the brain, some of which are involved in sleep. No known compounds have been reported to selectively target γ1- or γ3-containing GABAA receptors. Pharmacological assessments of this are conflicting, possibly due to differences in experimental models, conditions, and exact protocols when reporting efficacies and potencies. In this study, we evaluated the modulatory properties of five non-benzodiazepine Z-drugs (zaleplon, indiplon, eszopiclone, zolpidem, and alpidem) used in sleep management and the benzodiazepine, diazepam on human α1β2γ receptors using all three γ subtypes. This was accomplished using concatenated GABAA pentamers expressed in Xenopus laevis oocytes and measured via two-electrode voltage clamp. This approach removes the potential for single subunits to form erroneous receptors that could contribute to the pharmacological assessment of these compounds. No compound tested had significant effects on γ1-containing receptors below 10 μM. Interestingly, zaleplon and indiplon were found to modulate γ3-containing receptors equally as efficacious as γ2-containing receptors. Furthermore, zaleplon had a higher potency for γ3- than for γ2-containing receptors, indicating certain therapeutic effects could occur via these γ3-containing receptors. Eszopiclone modulated γ3-containing receptors with reduced efficacy but no reduction in potency. These data demonstrate that the imidazopyridines zaleplon and indiplon are well suited to further investigate potential γ3 effects on sleep in vivo.
Highlights
Specialty section: This article was submitted to Neuropharmacology, a section of the journal Frontiers in Neuroscience
The γ2 subunit is expressed throughout all stages of development, while γ1 subunit expression peaks around birth and γ3 subunit expression peaks in 2-week old animals (Laurie et al, 1992; Allen Institute for Brain Science, 2008) GABAA receptors with a γ1 subunit have been detected mainly in the amygdala, basal ganglia, hypothalamus, thalamus, and in astrocytes, while receptors with γ3 subunits show some expression in the basal ganglia, thalamus, and midbrain (Bovolin et al, 1992; Quirk et al, 1994; Pirker et al, 2000; Sieghart and Sperk, 2002; Hertz and Chen, 2010)
We systematically evaluated the pharmacology of five Z-drugs including the pyrazolopyrimidines, cyclopyrrolones, and imidazopyridines, along with diazepam on γ1, γ2, and γ3 concatenated pentameric GABAA receptors (Figure 2)
Summary
Specialty section: This article was submitted to Neuropharmacology, a section of the journal Frontiers in Neuroscience. Γ-Aminobutyric-acid type A (GABAA) receptors are ligand-gated ion channels that mediate most inhibitory responses in the brain. These receptors are made up of five building block subunits, and in mammals, there are nineteen identified subunits, α1-6, β1-3, γ1-3, δ, ε, θ, π, and ρ1-3 (Sieghart and Savic, 2018). Benzodiazepines and Z-drugs allosterically modulate GABAA receptors making the frequency of Cl− channel opening more likely. These drugs bind to the interface within the α(+) and γ(−) (Sigel and Buhr, 1997; Zhu et al, 2018) to reduce the brain’s excitability and are primarily prescribed for their effects as anxiolytics, hypnotics, anti-epileptics, and muscle relaxants. The interface between α(+)/γ(−) is believed to be sensitive to benzodiazepine binding in both γ1 and γ3 containing receptors, though some ligands might have lower potencies and/or efficacies because of amino acid sequence differences (Knoflach et al, 1991; Sieghart, 1995; Khom et al, 2006)
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