作者: Funato, Hiromasa ; Saitoh, Tsuyoshi ; Suzuki-Abe, Haruka ; Kaushik, Mahesh K ; Elhosainy, Asmaa ; Ishikawa, Yukiko ; Miyoshi, Chika ; Yanagisawa, Masashi ; Hotta-Hirashima, Noriko ; Kim, Staci J

Idiopathic hypersomnia (IH) is a chronic neurologic disorder with unknown mechanisms that result in long night-time sleep, daytime sleepiness, long non-refreshing naps, and difficult awakening presenting as sleep drunkenness. IH patients are typically diagnosed by shorter sleep latency on multiple sleep latency test (MSLT) along with long sleep time. Only symptomatic drug treatments are currently available for IH and no animal model to study it. Sleepy mice carry a splicing mutation in the Sik3 gene, leading to increased sleep time and sleep need. Here we used a mouse version of MSLT and a decay analysis of wake EEG delta power to validate the Sleepy mutant mouse as an animal model for IH. Sleepy mice had shorter sleep latency in the dark (active) phase than wild-type mice. They also showed lower decay of EEG delta density during wakefulness, possibly reflecting increased sleep inertia. These data indicate that the Sleepy mouse may have partial face validity as a mouse model for idiopathic hypersomnia. We then investigated the effect of orexin-A and the orexin receptor 2-selective agonist YNT-185 on the sleepiness symptoms of the Sleepy mouse. Intracerebroventricular orexin-A promoted wakefulness for 3 h and decreased wake EEG delta density after injection in Sleepy mice and wild-type mice. Moreover, Sleepy mice but not wild-type mice showed a sleep rebound after the orexin-A-induced wakefulness. Intraperitoneal YNT-185 promoted wakefulness for 3 h after injection in Sleepy mice, indicating the potential of using orexin agonists to treat not only orexin deficiency but hypersomnolence of various etiologies.

2020-10-01·Bioorganic Chemistry2区 · 化学

From orexin receptor agonist YNT-185 to novel antagonists with drug-like properties for the treatment of insomnia

2区 · 化学

Article

作者: Prchal, Lukas ; Janockova, Jana ; Dolezal, Rafael ; Soukup, Ondrej ; Kobrlova, Tereza ; Korabecny, Jan ; Konecny, Jan ; Mezeiova, Eva ; Karasova-Zdarova, Jana ; Benkova, Marketa

YNT-185 is the first known small molecule acting as orexin 2 receptor (OX₂R) agonist with implication to narcolepsy treatment, served as a template scaffold in generating a small set of seven compounds with predictive affinity to OX₂R. The design of the new small molecules was driven mostly by improving physicochemical properties of the parent drug YNT-185 in parallel with in silico studies, later suggesting their favorable binding modes within the active site of OX₂R. We obtained seven new potential OX₂R binders that were evaluated in vitro for their CNS availability, cytotoxicity, and behavior pattern on OX₂R. Out of them, 15 emerged as the most potent modulator of OX₂R, which, contrary to YNT-185, displayed inverse mode of action, i.e. antagonist profile. 15 was also submitted to an in vivo experiment revealing its ability to permeate through BBB into the brain with a short half-life.

2020-08-01·Life Sciences3区 · 医学

Exploring the role of orexin B-sirtuin 1-HIF-1α in diabetes-mellitus induced vascular endothelial dysfunction and associated myocardial injury in rats

3区 · 医学

Article

作者: Xu, Xiang ; Liu, Xiaoyong ; Yang, Rui ; Bi, Feng ; Li, Hu ; Dou, Xingkui ; Bai, Wenwei ; Zhu, Min

AIMThe present study explored the role and possible interrelationship between orexin B-sirtuin 1-HIF-1α signaling pathways in diabetes-mellitus induced vascular dysfunction and enhancement in myocardial injury.MATERIAL AND METHODSStreptozotocin (60 mg/kg) was employed to induce diabetes mellitus in male Wistar albino rats, which were kept for eight weeks. The vascular function was noted by assessing acetylcholine-induced relaxation in norepinephrine precontracted mesenteric arteries. The hearts were subjected to ischemia-reperfusion injury on the Langendorff apparatus. Myocardial injury was assessed by noting the release of CK-MB, cardiac troponin and measuring myocardial infarction. The levels of orexin B, sirtuin 1 and HIF-1α were measured. YNT-185 (orexin B type 2 receptor agonist), STR2104 (sirtuin 1 agonist) and EX527 (sirtuin 1 antagonist) were employed as pharmacological tools.RESULTSDiabetes led to significant development of vascular dysfunction and enhanced ischemia-reperfusion injury in isolated hearts. There was a significant decrease in the levels of orexin B, sirtuin 1 and HIF-1α in diabetic animals. Treatment with YNT-185 and/or STR2104 significantly attenuated the diabetes-induced increase in myocardial injury and vascular dysfunction. Co-administration of EX527 abolished the effects of YNT-185 suggesting orexin B-mediated effects may be through activation of sirtuin 1. Moreover, YNT-185-induced increase in the expression of sirtuin 1 and HIF-1α was also abolished in the presence of EX527.CONCLUSIONDiabetes-induced significant decline in orexin B levels in the plasma along with a decrease in the expression of sirtuin 1 and HIF-1α in the heart following ischemia-reperfusion injury may possibly contribute in exacerbating the myocardial injury and vascular dysfunction.

100 项与 YNT-185 相关的药物交易

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