Racing To Unlock The Secrets Of Serotonin

Schizophrenia is formidable--as are drugs that treat it. They cause an excessive drop in the chemical dopamine, a key to muscle movement, leading to such side effects as tremors and stiffness. But schizophrenics may soon stop getting the bad with the good. Janssen Pharmaceutica Inc., a unit of Johnson & Johnson, is seeking Food & Drug Administration approval of a drug called risperidone that avoids side effects. "It's a superb agent," says Dr. Richard L. Borison, chairman of psychiatry at the Medical College of Georgia in Augusta.

Risperidone is also a sign of the huge potential from research into a brain chemical called serotonin. Serotonin acts as a messenger, switching nerve cells on and off, and in so doing provokes subtle changes that modulate mood and behavior. Imbalances of the chemical may cause such psychiatric ills as anxiety, depression, addiction, and schizophrenia. The chemical is implicated, too, in migraine headaches and nausea. Cures for those represent markets worth billions, so big drug houses such as Glaxo, Eli Lilly, Merck, and Marion Merrell Dow are on the case. "Serotonin is one of the most fertile grounds for drug development," says Paul R. Hartig, vice-president for research at Synaptic Pharmaceutical Corp., a drug startup in Paramus, N.J.

Some of serotonin's promise already has been tapped. Prozac, the $1 billion drug developed by Eli Lilly & Co., combats depression by increasing levels of the chemical in the brain. It does this by slowing the removal of serotonin from synapses, the junction between nerve cells. But the future of such research may lie in an approach taken by Glaxo Group Research Ltd. to develop two other drugs. One, introduced in 1990, prevents vomiting in chemotherapy patients. Another, now awaiting fda approval, treats migraines. Rather than simply increasing serotonin levels, as Prozac does, these drugs mimic the specific effects serotonin has on cells.

LOCKS AND KEYS. It turns out that serotonin is involved in so many ailments because there's a network of slightly different receptors--the proteins that act as docking sites for the chemical on cells--all over the body. Whether serotonin causes blood vessels to constrict or directs release of a mood-altering compound depends on which receptor it binds to. For example, Dr. Bryan L. Roth, an associate professor at Case Western Reserve University School of Medicine in Cleveland, says that one receptor--called 5-HT1C--is found in two regions of the brain that are thought to be involved in obsessive-compulsive disorders, schizophrenia, and manic depression. A drug that binds only to this receptor could have great potential for treating these problems, he says.

New insights are being gained into serotonin, which was identified in 1948, because of breakthroughs in molecular biology. These techniques let researchers pinpoint genes that control the production of serotonin receptors. Using these genes, they can churn out copies of the proteins and study their structure. They then try to design drugs that bind tightly to the receptor--as a key fits a lock--and block or enhance its effect. Some 13 serotonin receptors have now been cloned--three times the number just two years ago. "It's this ability to pull out receptors, study them, then design drugs to fit each one that has people excited," says Hartig.

Researchers at Stanford University, McGill University in Montreal, the University of Washington, and elsewhere are trying to decipher what these proteins do. In September, some 500 scientists met in Houston to discuss such questions. More scientific papers were presented on the topic in late October at the annual Society for Neuroscience meeting in Anaheim, Calif.

In fact, "technology is moving so quickly that the clinical significance of these receptors is lagging behind," says Dr. Gary D. Tollefson, executive director of Lilly Research Laboratories. Researchers think that more than 20 serotonin receptors eventually will be located. Not all will be important in disease, says Tollefson, and it will be hard to tell which ones to ignore. Ditto for the job of designing drugs to interact with just one receptor: Some receptors "are so similar that it is almost unthinkable for a drug to interact with one and not the other," explains Albert Carr, Distinguished Scientist at Marion Merrell Dow Inc.

This raises the risk of unsuspected side effects. Glaxo Pharmaceuticals' migraine drug, for example, attaches to receptors on blood vessels surrounding the brain. This causes the vessels to constrict, alleviating the throbbing headache and other symptoms linked with migraines. But concern that the drug may also hit receptors on other blood vessels and lead to cardiovascular problems has stalled U.S. approval, says Hemant K. Shah, a drug industry analyst.

ANIMAL TESTS. Rather than design such drugs from scratch, it's quicker, for now, to screen those on lab shelves. Take Lilly. It has invested $12 million in Synaptic, which has cloned a collection of receptors and is helping develop serotonin for anxiety, depression, and other ills. Step one was to look at "stuff in the back room they didn't know they had," says Synaptic ceo Kathleen P. Mullinix. In nine months, this turned up four promising serotonin candidates, some of which are now in animal tests.

Glaxo also is capitalizing on the discovery of more serotonin receptors. Ondansetron, the drug that reduces vomiting in chemotherapy patients, targets a receptor called 5-HT3 that is found in both the gut and the brain stem. So, new research shows, the drug may affect receptors associated with anxiety and schizophrenia. Mike B. Tyers, director of pharmacology for Glaxo Group Research, says ondansetron or related drugs may help prevent some memory loss in Alzheimer's patients.

Designing serotonin drugs is proving to be harder than scientists had anticipated when fewer receptors were known. Still, recent studies suggest a role for serotonin in even more disorders--aggression, suicidal tendencies, and heart disease. So, what's now a dilemma for researchers may eventually be a boon, for patients and drugmakers both.