Counting sheep is the age-old, low-tech way of falling asleep.Counting atoms and base pairs is a higher-tech pathway to inducingslumber.

A somnifacient molecule isolated at the Scripps Research Institute inLa Jolla, Calif. counts 55 atoms, lined up as C18H35NO, andweighing in at 281 daltons. Its chemical name alone is soporific: cis-9,10-octadeceneoamide.

Yet, said Scripps' president, Richard Lerner, "it's a very simplecompound, trivial to make in the laboratory. And one can synthesizeit very simply and cheaply on a larger scale."

In today's Science he and his co-authors report "Chemicalcharacterization of a family of brain lipids that induce sleep." Thesemolecules, he emphasized to BioWorld Today, are natural products,essentially the body's own internal sheep-counting mechanism.

"As a public service," Lerner said, "I believe in following the WillySutton principle [go where the money is] in natural-productchemistry. Modern analytical methodologies are so powerful that weought to be able to return to man to find those natural products thathave escaped our earlier fishing-net detection."

He cited as precedent the way steroids were discovered: "Researchershad the observation that when women got pregnant, their arthritis gotbetter. So looking in their urine, they found what it was."

To discover the brain's own sleeping pill, as it were, the Scripps teamlooked not in urine but in cerebrospinal fluid (CSF), which drainscompounds that the brain secretes. They found it in felinessystematically deprived of sleep.

Stay-Awake Cats Secrete Sleep Substance

"We got 10 cooperative cats," Lerner recalled, "which we placed ona thin sort of conveyor belt that slowly moved them toward a pond ofwater. Cats don't like water, so they got up and left _ all night long."

He explained that this method was preferable to, say, loud music"because you don't want to isolate the exercise or the exasperationfactor."

By comparing the CSF of a sleep-deprived animal with fluidcollected after it had slumbered sufficiently, they expected to isolatea brain-made compound from the former not found in the latter.Which they did.

In traces penned by high-pressure liquid chromatography, they couldclearly see a peak in the no-sleep sample that was absent from thefull-sleep one, and varied with sleep intensity and duration.

To define the endogenous lipid's chemical composition and structure,the researchers subjected this peak product to the full armamentariumof sophisticated analytical chemistry, from electrospray mass analysisto various forms of mass spectrometry and chromatography, tonuclear magnetic resonance spectroscopy and chemical degradationprocedures, among others.

Having fully characterized the natural sleep-inducing product, theScripps team then synthesized the compound, and injected escalatingdoses of it (from 5 to 50 mg) into the bellies of 25 rats. The rodentsreceived this regimen during the dark phase of a 12-hour reversedlight-dark period.

Doses below 5 mg "produced no overt effect on spontaneousbehavior," Lerner's Science paper reported. But injections of 5 mgand above induced "long-lasting motor quiescence associated withclosed eyes and sedated behavior characteristic of normal sleep."This was not the effect of an anesthetic, Lerner emphasized, butnatural physiological slumber.

He and his team reasoned that if nature equipped the mammalianbrain with such a sleep-signaling family of molecules, there alsowould be tight feedback regulation, presumably enzymatic. "Whenwe found out what this sleep-promoting molecule was," Lernerobserved, "it was obvious to us that nature had invested a lot ofenzymology in synthesizing it."

Among other enzymes, his group found one that destroys the sleepcompound." He called it "a most interesting pharmacological targetfor the drug industry," and explained: "If this molecule causes sleep,inhibiting that enzyme will put people to sleep; if you induce theenzyme, you keep them awake."

He and his group have all but completed isolation of this off-switchenzyme, "which we estimate at about 40,000-dalton molecular weight_ we think." They are on the point of cloning its gene, and havealready made some inhibitors of it.

Lerner said potential applications of this basic discovery "revolve forthe moment around the enzyme. I would think that it has to do withmanipulating the levels of this stuff. People would use it either toincrease or decrease the compound for the purpose of staying awake,or going to sleep."

Its future, he said, "is broader" than merely giving insomniacs a goodnight's sleep, or helping long-distance truck-drivers stay awake at thewheel.

"It's possible that these very simple fatty-acid compounds areinvolved in very primitive things," Lerner mused, "like mood anddreaming and sleep, and so forth. I don't know; we'll have to see. It'searly days; hard to really say." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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