The orexin system is a critical regulator of sleep/wakefulness states, and the deficiency of orexin-producing neurons in lateral hypothalamus is associated with narcolepsy type 1 (NT1). NT1 is a severe neurological disorder characterized by excessive daytime sleepiness (EDS) and cataplexy. Stimulants (e.g. modafinil) and antidepressants (e.g. clomipramine) are used to treat EDS and cataplexy, respectively. Sodium oxybate and pitolisant show efficacy in both EDS and cataplexy but do not completely address the full extent and spectrum of narcolepsy symptoms in clinical practice. Narcolepsy-like symptoms such as wakefulness fragmentation were observed in orexin 2 receptor (OX2R) knockout (KO) mice, but not in orexin 1 receptor (OX1R) KO mice. This demonstrates an association between OX2R and narcolepsy symptoms, and suggests that selective activation of OX2R would potentially address the orexin deficiency in NT1 through reactivation of orexin neuronal signaling pathways. An OX2R agonist may provide better effectiveness for NT1 than current treatments by addressing the underlying deficiency of orexin in the brain.
We recently discovered a novel OX2R selective agonist, TAK-925. TAK-925 activated OX2R (EC50 = 5.5 nM) in in vitro calcium influx assays with > 5,000-fold selectivity against OX1R (EC50 > 30,000 nM). An electrophysiological study revealed that TAK-925 activated physiological OX2R in histaminergic neurons in mouse tuberomammillary nucleus. TAK-925 significantly increased wakefulness time in wild-type mice (≥ 1 mg/kg, s.c.), common marmosets (≥ 0.1 mg/kg, s.c.), and cynomolgus monkeys (≥ 1 mg/kg, s.c.), but not in OX2R KO mice, during their sleep phase.
The effect of TAK-925 on narcolepsy-like symptoms in orexin/ataxin-3 transgenic (TG) mice, a narcolepsy mouse model with orexin deficiency, was characterized using modafinil and clomipramine as controls. Modafinil (30 mg/kg, p.o.) and clomipramine (15 mg/kg, i.p.) were effective in reducing sleepiness or cataplexy-like episodes only, respectively, in orexin/ataxin-3 TG mice during their active phase. Under these conditions, TAK-925 (≥1 mg/kg, s.c.) significantly increased wakefulness time and completely recovered wakefulness fragmentation and cataplexy-like episodes in orexin/ataxin-3 TG mice.
In summary, the OX2R-selective agonist TAK-925 induced robust wake-promoting effects in mice and non-human primates during their sleep phase, and ameliorated narcolepsy-like symptoms, such as EDS and cataplexy, in orexin/ataxin-3 TG mice during their active phase. OX2R-selective activation may provide a new therapy for treatment of narcolepsy, and other diseases associated with hypersomnolence.
Support (If Any): This work was conducted by Takeda Pharmaceutical Company Limited.
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