Research zeros in on molecular destination of antidepressants

Side effects or not, Prozac and similar medications are helping millions of people live more satisfying lives. But scientists still aren’t sure exactly how the drugs work at the most basic molecular levels.

With a grant from the National Alliance for Research on Schizophrenia and Depression, UW Medical School researchers are aiming to find the answers. They hope the payoff will be even more effective drugs with fewer side effects.

The research effort, led by Arnold E. Ruoho and Nicholas V. Cozzi of the department of pharmacology, focuses on a protein that plays a role in balancing levels of serotonin, a brain chemical responsible for transmitting messages between nerve cells. Low serotonin levels have been implicated in depression, and abnormal levels may also be associated with eating disorders, obsessive-compulsive disorders, and possibly autism and anxiety-related disorders.

Under normal circumstances, a nerve cell releases a flood of message-bearing serotonin directed at a neighboring neuron. A protein structure on the nerve cell membrane, called the reuptake transporter, then shuts off the signal by reabsorbing the serotonin, pumping it back into the nerve cell for reuse.

“The transporter appropriately regulates the strength of the signal and how long it lasts,” said Cozzi. But when the system goes awry, serotonin levels can drop.

Some antidepressants raise serotonin levels by blocking the transporter, he said, while other drugs induce serotonin release.

Cozzi’s team is zeroing in on the specific site on the serotonin reuptake transporter to which antidepressant drugs must bind before they begin to work. Using state-of-the-art technology in chemistry, molecular biology and pharmacology, the researchers expect to identify the physical arrangement of the most basic structural building blocks–amino acids–of the binding site.

“When the molecular geometry of the binding site amino acids is known, new drugs can be designed to fit the site precisely,” he said. “This can result in extremely potent medicines with few side effects.”

The UW team is in the process of synthesizing new compounds that show promise as useful antidepressants.