Affordable Access

Publisher Website

Evaluation of the efficacy of the hypocretin/orexin receptor agonists TAK-925 and ARN-776 in narcoleptic orexin/tTA; TetO-DTA mice.

  • Sun, Yu1
  • Ranjan, Alok2
  • Tisdale, Ryan1
  • Ma, Shun-Chieh1
  • Park, Sunmee1
  • Haire, Meghan1
  • Heu, Jasmine1
  • Morairty, Stephen R1
  • Wang, Xiaoyu2
  • Rosenbaum, Daniel M2, 3
  • Williams, Noelle S2
  • De Brabander, Jef K2
  • Kilduff, Thomas S1
  • 1 Biosciences Division, SRI International, Menlo Park, California, USA.
  • 2 Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 3 Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Published Article
Journal of Sleep Research
Wiley (Blackwell Publishing)
Publication Date
Aug 01, 2023
DOI: 10.1111/jsr.13839
PMID: 36808670


The sleep disorder narcolepsy, a hypocretin deficiency disorder thought to be due to degeneration of hypothalamic hypocretin/orexin neurons, is currently treated symptomatically. We evaluated the efficacy of two small molecule hypocretin/orexin receptor-2 (HCRTR2) agonists in narcoleptic male orexin/tTA; TetO-DTA mice. TAK-925 (1-10 mg/kg, s.c.) and ARN-776 (1-10 mg/kg, i.p.) were injected 15 min before dark onset in a repeated measures design. EEG, EMG, subcutaneous temperature (Tsc ) and activity were recorded by telemetry; recordings for the first 6 h of the dark period were scored for sleep/wake and cataplexy. At all doses tested, TAK-925 and ARN-776 caused continuous wakefulness and eliminated sleep for the first hour. Both TAK-925 and ARN-776 caused dose-related delays in NREM sleep onset. All doses of TAK-925 and all but the lowest dose of ARN-776 eliminated cataplexy during the first hour after treatment; the anti-cataplectic effect of TAK-925 persisted into the second hour for the highest dose. TAK-925 and ARN-776 also reduced the cumulative amount of cataplexy during the 6 h post-dosing period. The acute increase in wakefulness produced by both HCRTR2 agonists was characterised by increased spectral power in the gamma EEG band. Although neither compound provoked a NREM sleep rebound, both compounds affected NREM EEG during the second hour post-dosing. TAK-925 and ARN-776 also increased gross motor activity, running wheel activity, and Tsc , suggesting that the wake-promoting and sleep-suppressing activities of these compounds could be a consequence of hyperactivity. Nonetheless, the anti-cataplectic activity of TAK-925 and ARN-776 is encouraging for the development of HCRTR2 agonists. © 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.

Report this publication


Seen <100 times