Discovery Hints at Multitude of New Targets for Drugs
DURHAM, N.C. -- A new study of how drugs plug into the human progesterone receptor in the cell supports a new and different view of how drugs and hormones act on steroid hormone receptors that trigger cellular responses.
The new view holds that steroid receptors are not merely on-off switches, but are far more complicated molecular "control panels" that could be manipulated by drugs customized to produce more targeted effects on the body, said the scientists who made the discovery. The drugs could cause the same receptor to trigger only certain of its normal effects in the body, but not others.
The finding, if confirmed, could point the way to a new wave of drugs with fewer side effects for contraception, hormone replacement therapy, breast and prostate cancer, inflammation, osteoporosis and endometriosis, said the researchers.
The scientists published their findings in the Aug. 6 issue of the Proceedings of the National Academy of Sciences. They are Brandee Wagner, Giuseppe Pollio and Donald McDonnell of the Duke University Medical Center departments of pharmacology and molecular cancer biology; Mansukh Wani, David Lee and C. Edgar Cook of the Research Triangle Institute (RTI), and Susan Leonhardt and Dean Edwards of the University of Colorado Health Science Center department of pathology. Their research was supported by the U.S. Public Health Service.
The researchers used living cells and test tube preparations to analyze how a range of compounds known to plug into the progesterone receptor affected its action.
Compounds that plug into receptors are known as ligands. Steroid receptors are complex proteins that are the principal switches activating cellular responses to steroid hormones. Steroid receptors reside deep in the cell's nucleus, activating genes that produce cellular responses. When a hormone or drug plugs into a receptor, that action changes the shape, or conformation, 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 multiple 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 action and drug development."
McDonnell uses a geometric analogy to explain how a single kind of steroid receptor found throughout the body can produce such different effects in different tissues by assuming different conformations.
"Let's say a receptor needs to be in a 'square' conformation to produce all the processes that it normally produces. If a ligand changes it into a 'round' conformation, some of the processes don't care, and they'll continue to operate. But others will not be triggered by a 'round' receptor, and they'll shut off." For example, he said, the same estrogen receptor influences a variety of processes throughout the body, including development of the female reproductive system, muscle and bone.
"We believe that nature has managed to produce a wide array of effects with a limited set of receptor molecules by altering the way the receptor functions in different cells," McDonnell said. "So, a receptor might interact with one set of factors in one cell, giving rise to one response. And it might interact with another set in another cell, giving rise to a whole different set of responses."
McDonnell said the discovery with the progesterone receptor could lead to improved hormone replacement therapy for post-menopausal women.
Currently, women receiving estrogen replacement therapy also take progesterone to reduce the likelihood of uterine cancer. The progesterones available now, however, are not selective, manifesting negative side effects in other tissues. According to McDonnell, discovery of the new class of progesterone receptor ligands indicates that it may be possible to develop a progesterone-like hormone that may be beneficial in the uterus but neutral elsewhere.
"The optimum would be a compound like a progesterone that would work only in the uterus to oppose the proliferative action of estrogen," he said. "But until now, researchers have believed that it wasn't possible. Now, however, this paper shows that we can do exactly the same with the progesterone receptor as with the estrogen receptor -- produce drugs that target only one tissue."
The new research also hints that a new progesterone-like compound of this new class might be developed as an oral contraceptive that does not cause the weight gain common with progesterone in oral contraceptives.