Identification of a Novel Series of Orexin Receptor

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Identification of a Novel Series of Orexin Receptor Proceedings of the British Pharmacological Society at http://www.pA2online.org/abstracts/Vol11Issue3abst083P.pdf Identification of a Novel Series of Orexin Receptor Antagonists with a Distinct Effect on Sleep Architecture: Orexin 2 Receptor Antagonism is Sufficient to induce Sleep D Hoyer 1,2 , EE Gee 3, GM Mang 4, M Fendt 5, LH Jacobson 2, E Legangneux 6, M Olorunda 6, G Calander 1,2 , D Abramowski 6, E Schuepbach 6, H Buerki 6, S Immobersteg 6, D Monna 6, D Langenegger 6, T Duerst 6, D Behnke 6, G Laue 6, S Ofner 6, S Hintermann 6, C Betschart 6. 1the University of Melbourne, Parkville, Vic, Australia, 2The Florey Institute of Neuroscience and Mental Health, Parkville, Vic, Australia, 3University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, Germany, 4University of Lausanne, Lausanne, Vaud, Switzerland, 5Otto-von-Guericke University, Magdeburg,, Germany, 6Novartis Institutes for BioMedical Research, Basel, Basel Stadt, Switzerland Orexin A & B (hypocretin 1 & 2) are produced by a few thousand neurons localized in the lateral hypothalamus, which project widely throughout the brain. Orexins / hypocretins activate two G-protein coupled receptors OX 1R and OX 2R. The orexin system modulates sleep-wake cycle, feeding and reward seeking behaviors. Orexin receptor antagonists are being developed for the treatment of sleep disorders. Positive proof of concept clinical studies were reported in primary insomnia with four different non subtype selective (also reported as dual) orexin receptor antagonists (DORAs), almorexant, suvorexant (MK-4305), SB-649868 and filorexant (MK-6096). However, the respective contribution of OX 1R and OX 2R in sleep regulation produced by orexin antagonists is a matter of debate. We initiated a drug discovery program with the aim of creating both DORAs and OX 2R selective antagonists (Betschart et al, 2013); sleep was tested using electrocorticogram/electroencephalogram and electromyogram recording in freely moving mice (n =10-12/ group). We report that a prototypical OX 2R selective antagonist IPSU (2-((1 H-Indol-3-yl)methyl)-9-(4-methoxypyrimidin- 2-yl)-2,9-diazaspiro[5.5]undecan-1-one, 25-100 mg/kg p.o.) induces sleep in C57BL/6J mice during the active phase (lights off) primarily by increasing non-REM (NREM) sleep, whereas the DORA suvorexant (12.5-50 mg/kg p.o.) induces sleep largely by increasing rapid eye movement (REM) sleep. In addition, IPSU (50 mg/kg) had no effect on sleep architecture when administered during the resting phase (lights on), whereas suvorexant (25 mg/kg) shifts the equilibrium towards REM. The effects of orexin A and almorexant were tested in C57BL/6J WT mice and in OX 1R, OX 2R or double OX 1R/OX 2R knock out mice, to investigate the respective roles of OX 1R and OX 2R receptors in orexin-induced locomotion and in sleep/wake regulation. Almorexant (50-200 mg/kg p.o.) attenuated intracerebroventricular orexin A- (3 µg) induced locomotion, demonstrating that almorexant specifically inhibits the actions of orexin in vivo . In addition, almorexant (25-300 mg/kg) dose-dependently increased REM and NREM sleep in C57BL/6J mice. Both almorexant and orexin A were ineffective in double OX 1R / OX 2R KO mice, indicating that their actions are mediated by the two known orexin receptors. In addition, both the orexin A-induced locomotion and the sleep induction by almorexant (100 mg/kg p.o.) were absent in OX 2R KO mice, but present in OX 1R KO mice (Mang et al, 2012). Kinetic studies were performed with IPSU and the fours DORAs at OX 1R and OX 2R expressed in cells using calcium accumulation (Callander et al., 2013). DORAs showed very slow kinetics at one and/or the other receptor, almorexant tending to become OX 2R selective, whereas suvorexant, filorexant and SB-649868 show slow kinetics at both OX 2R and OX 1R; in contrast, IPSU binds and dissociates rapidly at OX 1R / OX 2R, reaching equilibrium within minutes in contrast to the four DORAs. The slow kinetics of DORAs in vitro and probably in vivo suggest receptor occupancy to be longer lasting than predicted by pharmacokinetic studies. In conclusion, OX 2R activation mediates the stimulatory effects of orexin A on locomotion and antagonism of OX 2R is sufficient to promote sleep in mice. Thus, OX 2R selective antagonists may be beneficial for the treatment of insomnia, since they do not disrupt sleep architecture, whereas DORAs especially suvorexant, appear to stimulate primarily REM sleep. Betschart C et al., J. Med. Chem., 2013: 56, 7590 −7607. Callander G.E. et al., Front. Neurosci. 2013: 7:230. doi: 10.3389. Mang G.M. et al. Sleep, 2012: 35: 1625-1635. .
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