Combating sleep disorders: Scientists develop novel compound that regulates wakefulness
News Nov 18, 2015
Hiroshi Nagase, a Professor at the International Institute for Integrative Sleep Medicine, University of Tsukuba, collaborated with Masashi Yanagisawa and successfully developed a potent compound that promotes wakefulness and remedies the sleep disorder narcolepsy in model animals. Their work is published in the Journal of Medicinal Chemistry.
“Our achievement opens up a realistic avenue towards a novel medicine for narcoleptic patients. Immediately after our paper was published online, a narcoleptic patient in the US emailed us a letter of appreciation, which gave us further motivation to tackle this difficult technical challenge. We will make our best effort to keep optimizing the compound so that we will be able to provide a cure for narcolepsy in the near future.” Nagase says.
The compound works to mimic the action of a wake-promoting substance in our brain called “orexin.” Orexin, discovered in 1998 by Yanagisawa, is a neuropeptide that plays a central role in maintaining wakefulness. Its deficiency causes a serious sleep disorder called narcolepsy, in which patients experience excessive daytime sleepiness, often falling asleep uncontrollably. Patients also suffer from symptoms such as cataplexy (sudden loss of muscle tone triggered by emotion), vivid hallucinations when going into or out of sleep, and sleep paralysis. Orexin itself is proven to be effective in improving narcoleptic symptoms in model animals, but it cannot be readily used as a medicine because the blood-brain barrier prevents it from entering the brain, where orexin works by binding to its receptors. Instead, a small molecule mimicking orexin (orexin receptor agonist) should be useful as a therapeutic agent for narcolepsy.
Nagase and his colleagues designed and synthesized more than 2,000 compounds, and eventually discovered the first non-peptidic orexin receptor agonist, YNT-185. Giving YNT-185 to normal mice strongly promoted wakefulness. Moreover, YNT-185, when given to narcoleptic model mice, significantly ameliorated the symptom (unpublished data). This achievement is an important first step for development of a novel medicine to correct the fundamental disease mechanism of narcolepsy.
Note: Material may have been edited for length and content. For further information, please contact the cited source.
Nagahara T et al. Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists. Journal of Medicinal Chemistry, Published Online August 12 2015. doi: 10.1021/acs.jmedchem.5b00988
All in a Droplet: Atomic Resolution of ALS Protein ResolvedNews
Researchers have described atom-by-atom changes in a family of proteins linked to amyotrophic lateral sclerosis (ALS), a group of brain disorders known as frontotemporal dementia and degenerative diseases of muscle and bone.READ MORE
Pupil Size Couples to Cortical States to Protect Deep Sleep StabilityNews
Researchers have found that mice pupil size fluctuates during sleep. They also show that pupil size is a reliable indicator of sleep states.READ MORE
A Place to Think: Persistent neuronal activity in human prefrontal cortex links perception and actionNews
Neuroscientists have tracked the progress of a thought through the brain, showing clearly how the prefrontal cortex at the front of the brain coordinates activity to help us act in response to a perception.READ MORE