title: Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics.
abstract: BACKGROUND
  Narcolepsy, a disorder of rapid eye movement (REM) sleep, is characterized by excessive daytime sleepiness and cataplexy, a loss of muscle tone triggered by emotional stimulation. Current narcolepsy pharmacotherapeutics include controlled substances with abuse potential or drugs with undesirable side effects. As partial agonists at trace amine-associated receptor 1 (TAAR1) promote wakefulness in mice and rats, we evaluated whether TAAR1 agonism had beneficial effects in two mouse models of narcolepsy.
  
  
  METHODS
  In the first experiment, male homozygous B6-Taar1tm1(NLSLacZ)Blt(Taar1 knockout) and wild-type mice were surgically implanted to record electroencephalogram, electromyogram, locomotor activity, and body temperature, and the efficacy of the TAAR1 agonist, RO5256390, on sleep/wake and physiological parameters was determined. In the second experiment, the effects of the TAAR1 full agonist RO5256390 and partial agonist RO5263397 on sleep/wake, locomotor activity, body temperature, and cataplexy were assessed in two mouse narcolepsy models.
  
  
  RESULTS
  RO5256390 profoundly reduced rapid eye movement sleep in wild-type mice; these effects were eliminated in Taar1 knockout mice. The TAAR1 partial agonist RO5263397 also promoted wakefulness and suppressed nonrapid eye movement sleep. Both compounds reduced body temperature in the two narcolepsy models at the highest doses tested. Both TAAR1 compounds also mitigated cataplexy, the pathognomonic symptom of this disorder, in the narcolepsy models. The therapeutic benefit was mediated through a reduction in number of cataplexy episodes and time spent in cataplexy.
  
  
  CONCLUSIONS
  These results suggest TAAR1 agonism as a new therapeutic pathway for treatment of this orphan disease. The common underlying mechanism may be the suppression of rapid eye movement sleep.
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California.
authors.forename: Sarah W
authors.initials: SW
authors.lastname: Black
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California; Neuroscience, Ophthalmology and Rare Disease DTA, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schwartz
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California.
authors.forename: Tsui-Ming
authors.initials: TM
authors.lastname: Chen
authors.affiliation: Neuroscience, Ophthalmology and Rare Disease DTA, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Marius C
authors.initials: MC
authors.lastname: Hoener
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California. Electronic address: thomas.kilduff@sri.com.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kilduff
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004569:Electroencephalography; D004576:Electromyography; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009290:Narcolepsy / Q000188:drug therapy*; D010080:Oxazoles / Q000494:pharmacology; D035583:Rare Diseases; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D012895:Sleep, REM / Q000187:drug effects*; D064690:Wakefulness-Promoting Agents / Q000494:pharmacology*; D000095383:Trace Amine-Associated Receptors
chemical_list: D010080:Oxazoles; D043562:Receptors, G-Protein-Coupled; D064690:Wakefulness-Promoting Agents; D000095383:Trace Amine-Associated Receptors; C000596180:4-(3-fluoro-2-methylphenyl)-4,5-dihydrooxazol-2-ylamine
keywords: Cataplexy; Hypocretin; Mouse models; Orexin; Sleep; Trace amines