SCIENCE & TECHNOLOGY
STAYING AWAKE IS GETTING EASIER Wakefulness5 drug and advances in sleep research provide insight and treatments for narcolepsy E L I Z A B E T H K. W I L S O N , C&EN WEST COAST NEWS BUREAU
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OME YEARS AGO, A RECURRING
skit on the late-night comedy show "Mad TV" featured the Coffee Guy an overcaffeinated Java fiend whose bulging eyes, hyperactivity and uncontrollable shaking didn't stop him from gulping down pots of the stimulant beverage whenever he had the chance. While many people might envy the Coffee Guy's ability to stay awake, they probably wouldn't trade their sanity for it. Amphetamine-like drugs, while much
better than coffee at keeping people up and running, are even worse than caffeine in the side-effect department. Use too much, and you run the risk of addiction and psychosis. But although most sleep researchers would say the average workaholic should quit trying to subvert nature's sleep imperative with chemicals, there are situations when not sleeping is a good thing. The U.S.'s 125,000 narcoleptics, forwhom staying awake during the day can be impossible, rely on drugs to let them live more
normal lives. And the military would like to be able to give its soldiers the ability to keep alert during a crisis. Recently a new class of drugs that purports to allow a person to stay awake for several days at a time without dire side effects has made headlines. No euphoric highs, no crashing, and no addiction, report the studies on the drugs—just an alert "wakefulness." These drugs, of which there are currently only two, were originally developed at Louis Lafon Laboratories in France and have been available in Europe for a number of years. One of them, modafinil, was approved in the U.S. in 1998 for the treatment ofnarcolepsy Marketed by Cephalon under the name Provigil, modafinil has been hailed as a revolutionary narcoleptic therapy, the first new medication for the disorder in 30 years. Narcolepsy is most often characterized by an ovenvhelming, intractable sleepiness during the day People with the disorder may nod off at any time. Their work and personal lives suffer, and even treatment with amphetamines may be only partially effective. Narcoleptics may suffer from other symptoms, such as cataplexy where laughter or strong emotions such as anger or surprise may cause them to lose muscle control and become paralyzed for a few seconds. They may even collapse to the ground, unable to move yet still aware of what's going on around them. IT'S FOR THE SLEEPINESS, however, that drugs like modafinil offer a great deal ofhelp. The mechanism of action of modafinil and its close relative adrafinil (Olmifon), which still is available only in Europe, is unclear. But sleep researchers say there's no doubt that the drugs are quite effective, and quite different from anything else. A drug that keeps people awake seemingly without major consequences has, of course, raised concerns about its potential misuse by truck drivers hauling across the country students during finals, or executives trying to get ahead. And recently, the popular media, from ABC News to the New Torker, have speculated that the need for sleep could possibly be dispensed with altogether at some point in the future. That's a lot of hype, as-
No euphoric highs, no crashing, and no addiction, report the studies on the drugs—just an alert "wakefulness/ PF
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SCIENCE & TECHNOLOGY
SLEEP,
DEAR
SLEEP
New Drugs For Insomnia Have Fewer Side Effects
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hile many people would like to dispense with what they see as the time-wasting nuisance of sleep, another group—the world's insomniacs—would like nothing better than to spend eight blissful hours between the sheets. Sleep problems are more than just personal demons, however. The U.S. loses about $ U billion a year in lost productivity due to insomnia, and more than half of adults grapple occasionally with sleeplessness, according to the National Sleep Foundation. Drugs to make people sleep have evolved from an indiscriminate approach to the sophisticated targeting of specific brain receptors. And a new generation of anti-insomnia drugs edges even closer to the ideal suite of characteristics: good sleep, preservation of sleep stages that other medications can interfere with, no residual sleepiness the next day, and no dependence. Known broadly as nonbenzodiazepine hypnotics, this class of drugs includes Zolpidem (Ambien), approved by the Food & Drug Administration in 1993; the European insomnia drug zopiclone; and the newly approved zaleplon (Sonata), which hit the U.S. market in 1999. The drugs typically have short half-lives—Ambiens is only around two hours. Sonata has the shortest half-life of the group, a half hour to an hour, and can therefore be taken at any point that insomnia occurs, whether before going to bed or in the middle of the night.
The first sleep drugs were anesthetics like chloral hydrate, developed in the 1800s. In the early 1900s came the barbiturates, such as phenobarbital, which were better but still had great potential for
overdoses and addiction. More recently, the 1960s saw the introduction of benzodiazepines, which include some of the more famous sedatives like valium, xanax, and halcyon. It's now known that benzodiazepines act by binding to portions of a set of receptors for the neurotransmitter 7-aminobutyric acid (GABA). GABA is a central nervous system quieter. It is involved in reducing anxiety, as well as sedation. The binding of benzodiazepines at this receptor set, known as the GABAA receptor complex, helps increase GABA binding, boosting GABA's calming effects. However, barbiturates and benzodiazepines splash themselves indiscriminately across all five subunits of the GABAA receptor complex. The nonbenzodiazepines, however, bind to just one subunit of the complex, making their action much more specific. Pharmaceutical companies are developing more versions of this new type of drug. San Diego-based Neurocrine Biosciences is in Phase III clinical trials of its nonbenzodiazepine hypnotic, indiplon. Structurally similar to Sonata, indiplon is allegedly more potent. In efforts to characterize structures that bind to benzodiazepine receptors, researchers are turning to computers. For example, computational chemist Danni L Harris and colleagues at the Molecular Research Institute, a nonprofit research organization in Mountain View, Calif., have calculated a pharmacophore—a spatial arrangement of chemical structures—that sedating molecules should have in common. The pharmacophore consists of two proton-accepting atoms, such as an oxygen or nitrogen, a hydrophobic group, and an aromatic ring. Knowing this configuration of structures should aid in drug design.
serts sleep researcher Thomas E. Scam- I posure, there have been dramatic advances mell, assistant professor of neurology at in the understanding of the brain chemBeth Israel Deaconess Medical Center, istry involved in sleeping and staying Boston. He dismisses articles in the lay awake. That, in turn, has also given scienpress that claim "new drugs may make sleep tists a direction in which to proceed for unnecessary" as "completely out-of-condeveloping even more specifically tailored trol stuff like that." drugs for narcolepsy and other disorders that affect sleeping and waking. But amid the sometimes wild fantasizing, a lot of serious research questions are being asked and answered, making this a THE FIRST BIG breakthrough came in particularly fertile time for sleep research 1998, when two labs, led by molecular bias a whole. In the past few years, coincidologist Luis de Lecea at Scripps Research ing with the rise in modafiniTs public ex- I Institute and molecular genetics profes52
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Zopiclone (Imovane)
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B E T T E R S L E E P New-generation insomnia drugs more selectively target benzodiazepine receptors.
sor Masashi Yinagisawa at the University of Texas Southwestern Medical Center, independently discovered two previously u n k n o w n n e u r o t r a n s m i t t e r s . They're small peptides, 33 and 28 amino acids long, produced in the lateral hypothalamus by only a few thousand neurons. Because a prime center for the regulation of feeding behavior lies within the hypothalamus, the researchers initially focused on the peptides' possible roles in governing appetite. De Lecea's lab named the two peptides HTTP://WWW.CEN-ONLINE.ORG
hypocretin-1 and hypocretin-2, since the molecules resemble the gastrointestinal hormone secretin. Yanagisawa's group called them orexin-A and orexin-B, after orexis, the Greek word for appetite. The labs also showed that both orexins are derived from the same precursor molecule, prepro-orexin (or prepro-hypocretin), and that they bind to two receptors, OXR1 (Hcrtrl) and OXR2 (Hcrtr2). The names haven't yet been settled upon. Researchers soon realized that orexins play roles in many brain systems. In particular, orexin-producing neurons reach into sections of the brain that are especially important in regulating sleeping and waking. Then came another simultaneous discovery in 1999: Yinagisawa's lab and that of EmmanuelJ. Mignot, associate professor ofpsychiatry and behavioral sciences and director of the Center for Narcolepsy at Stanford University, and of Seiji Nishino, associate research professor of psychiatry and behavioral sciences and the center's associate director, found that disruptions in the orexin system are the long-sought cause of narcolepsy For years, Mignot and Nishino had been studying Doberman pinschers and Labrador retrievers to find a dog gene that, when mutated, causes a form of narcolepsy in these animals. The gene, it turns out, is none other than that for the orexin-B receptor, OXR2. Neurons in narcoleptic dogs' brains can produce orexins, but the receptors are defective.
Yanagisawa's group demonstrated a similar effect in mice. They knocked out the gene that codes for orexins, and the mice developed narcolepsy Then Mignot and Nishino found the smoking gun. They took samples of cerebrospinal fluid from a group of narcoleptics and discovered that they contained almost no orexins at all, compared with samples from a control group. From the studies of dogs, mice, and humans, scien-
Dramatic advances in the understanding of the brain chemistry involved in sleeping and staying awake have coincided with the rise modafinil's public exposure. tists now know that it doesn't matter whether an animal lacks working orexin receptors or the ability to produce the orexins themselves—either defect interrupts a critical cascade of biochemical reactions and leads to narcolepsy ALTHOUGH NARCOLEPSY in Doberman pinschers is genetic, human narcolepsy usually is not. Mignot and Nishino's group dissected brain tissue of deceased narcoleptics and found withered and damaged orexin neurons. "We confirmed the hypocretin neuron loss in the hypothalamus," Nishino says. The causes are likely some kind of outside influence—whether
a virus, head trauma, or autoimmune reaction—that destroys the neurons, he says. Thanks to this new knowledge, researchers now have a focused treatment strategy The most obvious approach would be to somehow supply the brain with orexin. However, the peptides are too large to cross the blood-brain barrier. So researchers would need to create small molecules that mimic orexins, a possibility drug designers are now exploring. Even further in the future, Nishino says, lie possibilities for grafting orexinproducing neurons into the brain, or for gene therapy Additionally with the knowledge that the lack of orexins causes narcolepsy comes the possibility for a in diagnostic test. Until now, there's been no way to easily confirm that someone has narcolepsy which usually develops in adolescence. "In some cases, it's taken 10 years before making the final diagnosis," Nishino says. Meanwhile, modafinil studies crossed paths with the new orexin research. In the 1980s, Lafon scientists had been studying their compound—2-{(diphenylmethyl)sulfinyl]acetohydroxamic acid, which they called adrafinil—as a potential antidepressant. As with numerous drug discoveries, the compound they developed had interesting properties that eclipsed the original intended effects. 'Although they weren't seeing an antidepressant effect, they saw an increased wakefulness in animals," says Sheryl L. Williams, Cephalon's senior director for
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