A quarter of all Americans, about 70 million, could use help from time to
time in getting a good night's sleep.
Sedatives can be useful, but can alter important brain functions that
normally occur during sleep -- and they can be addictive.
Now, some La Jolla scientists are attempting to build a better sleeping
pill that would modulate the chemicals in the brain that naturally bring
about sleep.
The Scripps Research Institute scientists want to regulate the flow of
oleamide, a substance they discovered two years ago that causes drowsiness.
A pill that modulates this chemical should yield a more natural sleep, said
Dale L. Boger, a molecular biologist at the institute. And that potentially
has great value, he says.
Although the conscious mind may be unaware of it, the brain does lots of
work during sleep, which is one of the most mysterious states of mental
activity. Thoughts about the day's events may be cemented into lasting
memories. There is dreaming, and regular patterns of electrical current are
generated by the brain.
But these events are interrupted by sedatives and hypnotic drugs that, he
says, "knock people out." For example, sedated sleepers do not wake up to
loud sounds as they would from normal sleep. People who use sedatives for
extended periods still require "catch-up" sleep as the body tries to
recover more normal sleep, Boger said.
And sedatives carry other risks. Many are addictive and act as depressants,
luring some to overdose and even die, he said.
"There's been a lot of interest in trying to identify natural substances
that might trigger or block sleep," said Gary Grunewald, chairman of
medicinal chemistry department at the University of Kansas.
"It is definitely worth pursuing."
To learn the secrets of oleamide, the Scripps researchers kept rats awake
for extended periods. They learned that as the time for sleep approaches,
the oleamide concentration builds in the brain. After a normal period of
sleep, the oleamide is broken down. It is changed by an enzyme into
harmless chemicals, and the sleeper awakes.
The Scripps team has developed synthetic molecules that block the enzyme.
In newly reported studies of rats, Boger and his colleagues administered
the synthetic molecules and were able to extend the rats' sleep. The
molecules work by fitting like a glove over the enzyme, preventing the
enzyme from snipping the sleep-inducing oleamide.
The enzyme-blockers are built by chemists mixing compounds at a lab bench.
The tests of the synthetic sleep-inducing agents on rats was reported in a
recent issue of the Journal of the American Chemical Society.
The growing ability to manipulate the oleamide pathway gives scientists
confidence that "we're doing things in the right way," said Steven J.
Henriksen, a neurobiologist on the Scripps team.
Some of the molecules they built as enzyme blockers actually induce sleep,
Boger said. And Henriksen says he can imagine a strategy that could use
oleamide itself as a soporific.
Researchers expect to test the compound in dogs and monkeys before trying
them on humans. Even so, Boger hopes such development will take only a few
years, depending on a couple of key factors.
The scientists want to build versions of the synthetics that might disperse
more easily in the body, Henriksen said. The existing synthetics have a
high lipid, or fat, content, making them hard to dissolve in the body.
And researchers want to look for side effects. They expect the induced
sleep to mimic natural sleep. Even so, there could be some unexpected
consequences or side effects, even with natural substances, Grunewald said.
Other evidence suggests that the oleamide may attach to sites on brain
cells where another chemical, serotonin, attaches to modulate levels of
excitability and calmness. One question is whether the oleamide would
somehow interfere with that process.
Oleamide holds other intrigue for investigators. Although they have not
begun any studies on the subject, they wonder whether oleamide plays a role
in coma.