Science : You are feeling very sleepy . . .

13 July 1996

San Francisco

WHEN you can’t sleep, pills that knock you out for a few hours can seem like
a godsend. But, as insomniacs know all too well, most sleeping pills are crude
sedatives that fail to mimic the refreshing effects of real sleep. Now,
in California think they have found a way to coax the brain into normal
using drugs that prevent a natural sleep-inducing molecule from being broken
down in the body.

Dale Boger and his colleagues at the Scripps Research Institute in La Jolla
have synthesised a group of compounds that slow down the destruction of the
sleep-inducing molecule, oleamide. The molecules closely resemble oleamide,
and act as decoys—fooling the enzyme that breaks it down into breaking
them down instead.

Boger’s team first identified oleamide in 1994. They discovered that the
molecule—a chain of 18 carbon atoms capped by a nitrogen group called an
amide—was unusually abundant in the cerebrospinal fluid of cats that had
been kept awake for 22 hours. Cats and rats injected with synthetic oleamide
quickly fell into a deep, natural sleep, and the bigger the dose, the longer
they slept. While the animals rested, oleamide was quickly broken down by an
enzyme called oleamide hydrolase. The team reasoned that tired animals produce
oleamide in large amounts to induce normal sleep, and that levels fall when
sleep is no longer needed.


It was not long before the researchers found oleamide in humans. They
realised that one way to exploit oleamide to induce sleep would be to slow down
its destruction. They synthesised 22 variations of it in the hope that one
act as a decoy, or “inhibitor” for the enzyme. Each variation was
different: for
example, one had an extra carbon atom, one a removed nitrogen, and yet another
had a twist in the long carbon chain. In test-tube experiments, they then
measured the rate at which oleamide hydrolase broke down oleamide in the
presence of each of these new molecules.

To their delight, eight of the molecules were powerful inhibitors of
hydrolase. But even more striking was the finding that one of the new
“compound 6”, was doubly effective. “Not only does it prevent the breakdown of
oleamide, but it appears to mimic oleamide and trigger sleep in animals in its
own right,” says Boger (Journal of the American Chemical Society, vol
118, p 5938). This double action would make it a potent drug.

Boger stresses, however, that the search for the perfect sleeping pill
is far
from over. Compound 6 has a long carbon chain that prevents it from dissolving
in water and therefore makes it difficult to deliver in small doses unless
it is
injected. And, Boger warns, many more studies will be needed before the
idea can
be tested in people.