The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold

BMC Neurosci. 2013 Aug 28;14:90. doi: 10.1186/1471-2202-14-90.


Background: Drugs targeting insomnia ideally promote sleep throughout the night, maintain normal sleep architecture, and are devoid of residual effects associated with morning sedation. These features of an ideal compound are not only dependent upon pharmacokinetics, receptor binding kinetics, potency and pharmacodynamic activity, but also upon a compound's mechanism of action.

Results: Dual orexin receptor antagonists (DORAs) block the arousal-promoting activity of orexin peptides and, as demonstrated in the current work, exhibit an efficacy signal window dependent upon oscillating levels of endogenous orexin neuropeptide. Sleep efficacy of structurally diverse DORAs in rat and dog was achieved at plasma exposures corresponding to orexin 2 receptor (OX2R) occupancies in the range of 65 to 80%. In rats, the time course of OX2R occupancy was dependent upon receptor binding kinetics and was tightly correlated with the timing of active wake reduction. In rhesus monkeys, direct comparison of DORA-22 with GABA-A modulators at similar sleep-inducing doses revealed that diazepam produced next-day residual sleep and both diazepam and eszopiclone induced next-day cognitive deficits. In stark contrast, DORA-22 did not produce residual effects. Furthermore, DORA-22 evoked only minimal changes in quantitative electroencephalogram (qEEG) activity during the normal resting phase in contrast to GABA-A modulators which induced substantial qEEG changes.

Conclusion: The higher levels of receptor occupancy necessary for DORA efficacy require a plasma concentration profile sufficient to maintain sleep for the duration of the resting period. DORAs, with a half-life exceeding 8 h in humans, are expected to fulfill this requirement as exposures drop to sub-threshold receptor occupancy levels prior to the wake period, potentially avoiding next-day residual effects at therapeutic doses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azepines / pharmacokinetics*
  • Dogs
  • Electroencephalography
  • Female
  • Humans
  • Immunoassay
  • Intracellular Signaling Peptides and Proteins / cerebrospinal fluid
  • Macaca mulatta
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuropeptides / cerebrospinal fluid
  • Orexin Receptor Antagonists*
  • Orexins
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Transgenic
  • Sleep / drug effects*
  • Sleep / physiology
  • Triazoles / pharmacokinetics*


  • Azepines
  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexin Receptor Antagonists
  • Orexins
  • Triazoles
  • suvorexant