Orexin, a neuropeptide produced by neurons in the lateral hypothalamus, regulates sleep and wakefulness. Orexin deficiency causes narcolepsy-cataplexy characterized by excessive sleepiness and cataplexy, a sudden loss of muscle tone triggered by emotion.
We previously showed that peripherally (i.p.) administered YNT-185 (40 mg/kg), an OX2R-selective agonist, ameliorates narcolepsy-cataplexy symptoms in mouse models. However, repeated i.p. of YNT185 can be stressful and the effective dose for oral administration (p.o.) is too high (4000 mg/kg) to ameliorate the symptoms. Here we further optimized YNT-185 (EC50 ≈ 28 nM) and produced YNT-X, which increased intracellular Ca2+ in lower concentrations in OX2R-transfected cells. The EC50 value was 1.1 nM (OX2R) and the maximum response was similar to orexin in vitro. The response was inhibited by EMPA, an OX2R antagonist. In vivo, YNT-X p.o. increased wake time in wildtype mice in a dose-dependent manner, with the effective dose of 2.5-10 mg/kg, which is several hundred times lower than YNT-185. Our results suggest that YNT-X may be useful as mechanistic, oral therapy for narcolepsy-cataplexy.