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.