New drug knocks insomnia on the head

A new drug that can overcome insomnia without leaving users feeling hungover the following day is being tested in the US.

Although the average doctor's medicine bag is full of drugs capable of sending patients off to sleep, such as diazepam a widely-used benzodiazepine, these agents invariably have serious side effects, including dependency and ensuing daytime difficulties with memory and cognition.

This occurs because, as well as activating sleep-inducing circuits in the brain, these agents also suppress the activity of nerve cells responsible for learning, memory and attention.

And because, by necessity, the drugs need to have a long duration of action to ensure that, once asleep, the patient remains that way, these other unwanted effects spill-over into the following day's activities, impairing performance.

But now scientists have uncovered a class of agent that can trigger sleep exclusively, without hampering other brain activities. Known as DORA-22, short for "dual orexin receptor antagonist", the new agent was first synthesised last year by scientists at the pharmaceutical company Merck, who have now begun testing the drug, with promising results, on rats and monkeys.

Writing in Science Translational Medicine, Merck researcher Jason Uslaner and his colleagues have compared the effects on memory, attention and sleep of DORA-22 and the existing sedative agents diazepam, eszopiclone and zolpidem.

Rats given the latter drugs were significantly impaired in recall tests and monkeys had poorer working memory and attention. In both animals these side effects occurred at doses much lower than those required to affect sleep. But administration of DORA-22 induced increased sleep at doses 30 times lower than those needed to produce any similar changes in learning, memory or attentional abilities.

DORA-22 blocks the action of two nerve signals called orexins, which were discovered in the late 1990s as potent and discrete "wake-up" signals in the brain.

They are produced by a relatively small number of nerve cells located in a discrete part of the brain's hypothalamus where they connect almost exclusively to other sleep-related brain regions. Consequently, they are an ideal target for therapeutic intervention and on this basis the Merck scientists recommend taking the research forward to assess whether human insomniacs will benefit...