compound
We initially developed four hybrid analogues of this compound with an
array of biological activity ranging from inactive controls to highly
potent derivatives resulting in, α5-SOP002 (Figure 1 A-C, see also
supplementary scheme 1).
The structure of the α5 subunits contained in the α5
GABAAR was modelled and later used to generate the
GABAAR subtype containing two α5, two β3 and one γ2
subunits. Once a reliable model was obtained, our key compound,
α5-SOP002 was docked into the interface of subunit α5 (Figure 1 (D-H))
and subunit γ2, obtaining the best binding mode with a VlsScore of
-20.35.
Overall, α5-SOP002 indicated good aqueous solubility and good
blood-brain barrier penetration as evidenced from the spatial memory
recall experiments in rats following intraperitoneal injection (i.p.)
(supplementary Figure 1). The supplementary section, which comparesin vivo spatial memory tests (Becker et al., 1980) and in
vitro paired whole recording data from 25-28 day old rats using
α5-SOP002 and the published analogue L-655,708 (a similar compound to
α5IA originally developed by Merck Sharp and Dome (UK) and available
from Tocris (UK) were discribed. In vivo , spatial memory recall
experiments were not repeated in the mouse lines due to the conclusions
reached from the results (see below).