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MEDICINE: Sweeter dreams BioNews 24 May 2000 Insomniacs take heart. The choice may no longer be between black-out pills and all-night TV. Chemists at the Scripps Research Institute in La Jolla, California, have developed a new molecule that could induce 'normal' sleep, without the unwelcome side effects of current sleeping pills. Such side effects can be severe. Sedatives administered for sleeping disorders generally turn down activity in the central nervous system, throwing a blanket over the whole of the brain's communication with the body. This brings sleep that is more like anaesthesia than normal 'physiological' rest. It can leave the patient utterly wiped out and unable to respond to the sort of disturbances that wake up normal sleepers, often for good reason. And some sleeping pills are potentially addictive - perhaps leading to depression over prolonged periods. Should the thoughts of a depressed person then turn to suicide, an overdose of sleeping pills can supply the means. Normal sleep seems to work quite differently - researchers think it is triggered by sleep-inducing substances in the brain. In 1995, Benjamin Cravatt and his co-workers at the Scripps Institute isolated a molecule called 'oleamide' from sleep-deprived cats, which could induce sleep in rats. Oleamide 'improves' sleep - shortening the 'dropping-off' period and promoting deep slumber - without the deadening effects of sedatives. Oleamide accumulates in the brain when sleep approaches. But using oleamide as a sleep inducer in laboratory tests has produced mixed results. During sleep itself, an enzyme called fatty acid amide hydrolase (FAAH) breaks down oleamide. So the Scripps team thought that this enzyme might make a better target - if FAAH can be prevented from doing its job, then sleep should follow. In 1996 Cravatt, with chemist Dale Boger and his colleagues, developed molecules capable of blocking the FAAH enzyme, up to a point. They now describe blocking agents that are up to a thousand times more potent, in the Proceedings of the National Academy of Sciences [9 May 2000]1. The new molecules have a correspondingly greater potential as sleep aids. Enzyme inhibitors typically appear like the enzyme's intended target (in this case oleamide) but they cannot be broken down. This jams the enzyme's jaws, preventing it acting on the real targets. FAAH transforms the chemical group sitting at one end of the chainlike oleamide molecule. To fool the enzyme, Boger and colleagues synthesized different chains with deceptively similar baits at the end. FAAH also breaks down a related molecule in the brain called 'anandamide', which affects communication between neurons. Anandamide appears to act as a pain suppressor, so FAAH inhibitors could also provide pain-relieving drugs - by protecting anandamide as it exerts its analgesic effect. The new enzyme inhibitors have been studied only in the test tube so far. The true test will come in living creatures: it is likely that the new molecules will induce sleep and analgesia but it remains to be seen whether there will be any other side effects. Philip Ball Copyright Nature News Service 2000 |
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