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Fig. 6
Candidate AOPs for several of the compounds we investigated in this study. The left set of events in blue/ purple hues represent the binding of ligands to their respective binding sites. Picrotoxin, bicuculline, DMCM, clobazam, and amoxapine are rendered in 2D as examples for the different binding sites and for the experimental pipeline. Different allosteric sites can mediate functional agonism and antagonism as well as NAM and PAM effects, which induce typically a change in GABA-elicited current. The proposal reflects a coarse grain model which requires further details to generate complete AOPs. Here, green hues indicate the late molecular and the cellular scales at which the ligand binding leads to changes in inhibitory transmission and then to changes in neuronal firing patterns. The red hues represent the organ and organism scales, at which changed neuronal firing patterns impact on network activity and thus on EEG and ultimately lead to organism responses such as seizures, convulsions, or paradoxical responses such as agitation that are often observed for GABAAR targeting “tranquilizers.” The assays that were used in this study at the molecular, cellular, tissue, and organism scales are integrated at the bottom of the graph. Ligand examples for each pathway are boldfaced and underlined for agents with known seizurogenic properties, boldfaced for strong candidates (meeting at least two criteria), and in standard font for the remaining examples