Hops compounds modulatory effects and 6-prenylnaringenin dual mode of action on GABAA receptors

Humulone Modulation of GABAA Receptors and Its Role in Hops Sleep-Promoting Activity

“…These findings correlate with the earlier proposed differences between 6PN and IXN in molecular docking at GABA A receptor α1β2γ2 isoform where a higher binding free energy was predicted for 6PN at both α1+β2and α1+γ2interfaces (Benkherouf et al, 2020). Consistently, 6PN was remarkably more efficient than IXN and humulone in displacing [ 3 H]Ro 15-4513 binding to the classical benzodiazepine binding site in GABA A receptors suggesting a favorable binding site for 6PN at α1+γ2interface (Benkherouf et al, 2019(Benkherouf et al, , 2020. However, it is unlikely that 6PN additive modulation with IXN and humulone occurs via α1+γ2interface due to 6PN insensitivity to flumazenil antagonism and hence the lack of involvement of the classical benzodiazepine site in its allosteric activity.…”

“…Furthermore, alpha acids were found to exhibit sedative and hypnotic properties ( Zanoli et al, 2005 ; Schiller et al, 2006 ), indicating their major role in hops’ sleep-promoting activity previously reported in animal models ( Bravo et al, 1974 ; Lee et al, 1993 ; Franco et al, 2012a , 2014 ) and humans ( Vonderheid-Guth et al, 2000 ; Dimpfel and Suter, 2008 ; Franco et al, 2012b ). This activity is attributed to the positive modulation of γ-aminobutyric acid type A (GABA A ) receptor function demonstrated earlier with hops extracts ( Aoshima et al, 2006 ; Sahin et al, 2016 ) and alpha acid fractions ( Benkherouf et al, 2020 ).…”

“…We reported earlier that humulone potentiates GABAinduced [ 3 H]EBOB displacement in native GABA A receptors at low micromolar concentrations (Benkherouf et al, 2020). Hence, it was essential to demonstrate humulone's ability in modulating of GABA A receptor function using electrophysiological measurements.…”

“…The presence of several weak modulators that potentially compete for the same binding site as humulone may reduce the potency of alpha acids. This is because alpha acids contain cohumulone and adhumulone, which are structurally very similar to humulone and display weak modulatory effects on GABA A receptors (Benkherouf et al, 2020).…”

“…In the quest to uncover the constituents responsible for the sedative and hypnotic properties of hops, we earlier isolated hops fractions with semipreparative liquid chromatography and revealed individual components that modulate [ 3 H]EBOB binding to native GABA A receptors with variable potency. The humulone fraction was found to display potent modulatory activity at low micromolar concentrations in rat forebrain membranes (IC 50 = 3.2 ± 0.4 μM) with insensitivity to flumazenil antagonism and low potency on the benzodiazepine binding site ( Benkherouf et al, 2020 ). This prompted further exploration of its role in hops enhancement of GABA A receptor function.…”