Discovery Hints At Multitude Of New Targets For Drugs

tion, of the receptor. Previously, most scientists believed that this conformational change could only produce an on-off response.

Some of the new findings supported that early view. The researchers found that some of the test compounds were "agonists" of the receptor, switching it on. And others were "antagonists," blocking its action.

However, surprisingly, they discovered a new class of compounds that behaved differently from either of the first two classes. The compounds functioned as agonists in some cellular contexts, but as antagonists in others.

Discovery of this third class has broad clinical implications, said Donald McDonnell, an associate professor of pharmacology in the Duke medical center. The finding extends earlier work in his laboratory showing that the estrogen receptor, a distinctly different kind of steroid receptor, also shows similar mulitple modes of interaction with drugs or hormones.

"The discovery of such complexity in one receptor type is a phenomenon; the discovery of two is a paradigm," said McDonnell. "It's likely that these findings will extend to other receptors, such as the male androgen receptor," he said.

According to McDonnell, the discovery of new ways to affect such receptors could produce significant changes in the strategies by which pharmacologists seek new drugs to modulate them.

"To target drugs to one body tissue, pharmacologists have traditionally looked for subtypes of a receptor unique to that tissue," he said. "They could then design compounds that would select one or another subtype. But if there was only one kind of receptor, they were stuck.

"But now, our laboratory and others are showing that different compounds acting through the same receptor can manifest different biologies in different cells. We believe this extremely exciting realization will bring the next wave in the understanding of hormone a

Contact: Karyn George
Duke University

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