Sesquiterpenes and sesquiterpenoids harbor modulatory allosteric potential and affect inhibitory GABAA receptor function in vitro

Naturally occurring compounds such as sesquiterpenes and sesquiterpenoids (SQTs) have been shown to modulate GABAA receptors (GABAARs). In this study, the modulatory potential of 11 SQTs at GABAARs was analyzed to characterize their potential neurotropic activity. Transfected HEK293 cells and primary hippocampal neurons were functionally investigated using electrophysiological whole‐cell recordings. Significantly different effects of β‐caryophyllene and α‐humulene, as well as their respective derivatives β‐caryolanol and humulol, were observed in the HEK293 cell system. In neurons, the concomitant presence of phasic and tonic GABAAR configurations accounts for differences in receptor modulation by SQTs. The in vivo presence of the γ2 and δ subunits is important for SQT modulation. While phasic GABAA receptors in hippocampal neurons exhibited significantly altered GABA‐evoked current amplitudes in the presence of humulol and guaiol, negative allosteric potential at recombinantly expressed α1β2γ2 receptors was only verified for humolol. Modeling and docking studies provided support for the binding of SQTs to the neurosteroid‐binding site of the GABAAR localized between transmembrane segments 1 and 3 at the (+α)‐(‐α) interface. In sum, differences in the modulation of GABAAR isoforms between SQTs were identified. Another finding is that our results provide an indication that nutritional digestion affects the neurotropic potential of natural compounds. The modulatory potential at GABAA receptors of 11 sesquiterpenes and sesquiterpenoids (SQTs) was analyzed. To characterize their potential neurotropic activity, electrophysiological whole‐cell recordings from transfected HEK293 cells and primary hippocampal neurons were performed. Phasic and tonic GABAA receptor configurations present in vivo in one neuron account for differences in receptor modulation by SQTs. Moreover, nutritional digestion affects the neurotropic potential of SQTs. Molecular docking studies revealed that binding to the lipophilic interface forming the neurosteroid‐binding site is possibly preferred over the diazepam‐binding site.