Conceptual model for DORA OX2R occupancy and efficacy based on pharmacokinetic and receptor-binding properties. A. Normal and disrupted sleep relative to OX-A levels (solid black line) during the human inactive period (gray shading). Wake during disrupted sleep (red dashed line) is punctuated by brief periods of wake after sleep onset, while normal sleep (blue dashed line) follows orexin levels. B. Time course of the sleep-promoting efficacy of benzodiazepine-based GABA-A receptor modulators (BzRMs). Following treatment (gray arrow), active wake diminishes as GABA-A receptor occupancy (black dotted line) exceeds that required for sleep efficacy, 27% (horizontal black dashed line) . Red hatched area, difference from normal active wake (blue dashed line). Residual effects (R.E.) during the subsequent waking period as compound levels sufficient for GABA-A receptor occupancy are exceeded following the normal 8-h resting period. C. Efficacy time course of non-benzodiazepine GABA-A receptor modulators (non-BzRMs). GABA-A receptor occupancy (black dotted line) induced by sub-optimal doses of non-BzRMs are not sufficient to engage these receptors allowing early morning awakenings (E.M.A.). Yellow hatched area, difference from normal active wake (blue dashed line). D. DORAs, sufficiently engineered for optimal pharmacokinetic and receptor-binding kinetics, induce OX2R occupancies (black dotted line) sufficient to block the wake-promoting properties of orexin throughout the 8-h resting period and, given the high level of OX2R occupancy required for sleep-promoting efficacy, avoid residual effects persisting into the subsequent waking period even in the presence of moderate levels of compound exposure.
Gotter et al. BMC Neuroscience 2013 14:90 doi:10.1186/1471-2202-14-90