Mechanism of action of our key compound α5-SOP002
From computational modelling, we showed that α5-SOP002 docked into the
interface of the α5 and γ2 subunits, indicating that it works via the
benzodiazepine binding site (composed of a γ2 and either α1, α2, α3 or
an α5 subunit of the GABAAR). Normally, binding of
benzodiazepines to these sites causes a conformational change of the
receptor increasing the receptor’s affinity for GABA, resulting in an
enhanced inhibitory (hyperpolarising) effect mediated via
Cl- flux (Sieghart, 1995). However, NAMs, such as
α5-SOP002, when bound to the same GABAAR sub-typesdecrease the influx of Cl- which leads to
depolarisation of the membrane and a decreased net inhibitory
effect (Haefely et al., 1993). The data obtained from various HEK
cell-lines constructed to contain specific GABAAR
subunits and electrophysiological recordings performed, provided
evidence to suggest that the developed compound, α5-SOP0002 specifically
acted as a negative allosteric modulator at α5 GABAARs
and had no effect on α1 or α2 subunit-containing
GABAARs. However, this does not preclude an action of
α5-SOP0002 as a NAM in native GABAARs where the synaptic
colocalisation of the α subunits could result from a combination of the
insertion of either two identical α subunits, or from insertion of a
single receptor sub-type that contains two different α subunits. The α
subunit that is adjacent to the γ2 subunit dominates the pharmacological
profile of the receptor as suggested previously by binding studies on
double immunopurified α1/α5 GABAARs (Araujo et al.,
1999). Thus, we suggest that α5-SOP002 acts by specifically binding at
the interface of α5 and γ2 subunits, which determines a unique
pharmacological profile of this compound.