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).