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
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 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.
For males, the research indicates it may be possible to develop a testosterone-like
compound that can treat muscle-wasting diseases, but not cause hair loss,
acne and aggression that testosterone treatment produces, McDonnell said.