title: Orexin receptor antagonists differ from standard sleep drugs by promoting sleep at doses that do not disrupt cognition.
abstract: Current treatments for insomnia, such as zolpidem (Ambien) and eszopiclone (Lunesta), are γ-aminobutyric acid type A (GABAA)-positive allosteric modulators that carry a number of side effects including the potential to disrupt cognition. In an effort to develop better tolerated medicines, we have identified dual orexin 1 and 2 receptor antagonists (DORAs), which promote sleep in preclinical animal models and humans. We compare the effects of orally administered eszopiclone, zolpidem, and diazepam to the dual orexin receptor antagonist DORA-22 on sleep and the novel object recognition test in rat, and on sleep and two cognition tests (delayed match to sample and serial choice reaction time) in the rhesus monkey. Each compound's minimal dose that promoted sleep versus the minimal dose that exerted deficits in these cognitive tests was determined, and a therapeutic margin was established. We found that DORA-22 has a wider therapeutic margin for sleep versus cognitive impairment in rat and rhesus monkey compared to the other compounds tested. These data were further supported with the demonstration of a wider therapeutic margin for DORA-22 compared to the other compounds on sleep versus the expression of hippocampal activity-regulated cytoskeletal-associated protein (Arc), an immediate-early gene product involved in synaptic plasticity. These findings suggest that DORAs might provide an effective treatment for insomnia with a greater therapeutic margin for sleep versus cognitive disturbances compared to the GABAA-positive allosteric modulators currently in use.
authors.affiliation: Merck & Co. Inc., WP46-100, 770 Sumneytown Pike, P. O. Box 4, West Point, PA 19486, USA. jason_uslaner@merck.com
authors.forename: Jason M
authors.initials: JM
authors.lastname: Uslaner
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Tye
authors.forename: Donnie M
authors.initials: DM
authors.lastname: Eddins
authors.forename: Xiaohai
authors.initials: X
authors.lastname: Wang
authors.forename: Steven V
authors.initials: SV
authors.lastname: Fox
authors.forename: Alan T
authors.initials: AT
authors.lastname: Savitz
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Binns
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Cannon
authors.forename: Susan L
authors.initials: SL
authors.lastname: Garson
authors.forename: Lihang
authors.initials: L
authors.lastname: Yao
authors.forename: Robert
authors.initials: R
authors.lastname: Hodgson
authors.forename: Joanne
authors.initials: J
authors.lastname: Stevens
authors.forename: Mark R
authors.initials: MR
authors.lastname: Bowlby
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Tannenbaum
authors.forename: Joseph
authors.initials: J
authors.lastname: Brunner
authors.forename: Terrence P
authors.initials: TP
authors.lastname: Mcdonald
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kuduk
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001288:Attention / Q000187:drug effects; D053961:Azabicyclo Compounds / Q000008:administration & dosage / Q000494:pharmacology; D002755:Choice Behavior / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003975:Diazepam / Q000008:administration & dosage / Q000494:pharmacology; D000069582:Eszopiclone; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064446:Orexin Receptors; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021641:Recognition, Psychology; D012890:Sleep / Q000187:drug effects*; D013647:Task Performance and Analysis; D013997:Time Factors; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D053961:Azabicyclo Compounds; D003598:Cytoskeletal Proteins; C581638:DORA-22; D006993:Hypnotics and Sedatives; D009419:Nerve Tissue Proteins; D064446:Orexin Receptors; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014230:Triazoles; C092069:activity regulated cytoskeletal-associated protein; D005680:gamma-Aminobutyric Acid; D000077334:Zolpidem; D003975:Diazepam; D000069582:Eszopiclone