Richard B. Mailman talks with
ScienceWatch.com and answers a few questions about
this month's New Hot Paper in the field of Pharmacology
& Toxicology. The author has also sent along
images of their work.
Article Title: Functional selectivity and classical
concepts of quantitative pharmacology
Authors: Urban, JD, et al.,
Journal: J PHARMACOL EXP THER
Volume: 320
Issue: 1
Page: 1-13
Year: JAN 2007
* Univ N Carolina, Neurosci Hosp, Sch Med, CB 7160,7011 NC,
Chapel Hill, NC 27599 USA.
* Univ N Carolina, Curriculum Toxicol, Chapel Hill, NC
27599 USA.
* Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599
USA.
* Univ N Carolina, Sch Med, Dept Neurol, Chapel Hill, NC
27599 USA.
(addresses have been truncated)
Why do you think your paper is highly cited?
There are three major reasons why this paper may have had an impact. First,
in pharmacology and toxicology (and all the disciplines that use drugs as
tools), the terms agonist, antagonist, etc., have been defined precisely
within a narrow context. As an example, a compound that was an agonist was
expected to be an agonist at every function mediated by its target
receptor. Similarly, an antagonist would always block every function
mediated by an agonist at the target receptor.
Functional selectivity changes this, and posits that some drugs (or, more
generally, some ligands) may differentially affect functions mediated by a
single receptor. At an extreme, a drug might be both a full agonist and a
pure antagonist at two different functions mediated by a single receptor. I
think this paper has provided a convenient source reference offering both
examples and a discussion of possible mechanisms.
Second, functional selectivity is a natural outgrowth of the increased
understanding of the complexity of receptor signaling mechanisms elucidated
over the past two decades. The awareness of how receptor partners influence
the consequence of ligand-receptor interaction is an exciting research
arena.
Third, from a drug discovery point of view, differential signaling of a
single ligand working through a single receptor clearly suggests the
potential for novel drugs acting at “old” targets. One of the
examples I highlighted in the article was an antipsychotic drug that may be
the first example of novel clinical effects evoked largely by receptor
functional selectivity. If true, this opens unexpected vistas for drug
discovery.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
As noted above, this paper describes a new synthesis of knowledge that
changes a classical concept of pharmacology and drug action. The concept of
functional selectivity resulted from experimental discoveries made
relatively contemporaneously in a number of laboratories worldwide.
Would you summarize the significance of your paper in
layman’s terms?
Scientists have often used a “lock-and-key” metaphor to explain
how drugs work. Some drugs do not fit the lock (wrong make of key). Other
drugs selectively bind to a target receptor (i.e., “the key fits the
lock”). Two things can happen: some drugs (“keys”) turn
the lock and allow the door to open—in pharmacological terms, these
drugs are called agonists. Other drugs (“keys”) can go into the
lock, but cannot open the door, and by being in the lock, they prevent
other drugs (different “keys”) from being inserted—such
drugs are called antagonists.
"...this
paper describes a new synthesis of
knowledge that changes a classical
concept of pharmacology and drug
action."
In classical pharmacological theory, a single key would work the same way
in a given lock no matter what type of door the lock was installed in. If
one were to try and adapt this classic metaphor to functional selectivity,
one might say that the latch mechanism and type of door also play major
roles in whether the lock works. In reality, the rigid
“lock-and-key” metaphor, as postulated by Dutch biologist Emil
Fisher in 1894, has probably outlived its usefulness.
How did you become involved in this research, and were
there any problems along the way?
In studying the off-site action of a drug we developed in the late 1980s,
my lab found a pattern of drug effects that was apparently inexplicable by
the current dogma. Once experimental errors and alternate mechanisms had
been ruled out, we tried to put the observations in the context of the new
knowledge about receptor signaling emerging from many laboratories. The
resulting hypothesis (“functional selectivity”) had immediate
appeal to us, but for several years, it was difficult to not have this idea
dismissed as an artifact. Persistence by us and several other labs and
authors eventually led to a wider acceptance of this idea (albeit, it has
taken more than a decade).
Where do you see your research leading in the
future?
I see three major areas of research that are of great interest. The first
is to understand what characteristics of a ligand cause it to signal
differentially. Second, it is important to elucidate the receptor signaling
partners for different signaling pathways that play a role in the
expression of functional selectivity. Third, many share our view that
knowledge about this phenomenon can lead to the discovery of drugs that can
cause novel clinical effects (e.g., leaving desired therapeutic effects
alone but decreasing side effects mediated by the targeted receptor).
Do you foresee any social or political implications for
your research?
Although the notion of functional selectivity is likely to have
implications for both understanding drug mechanisms and for novel drug
discovery, there will not be social or political implications.
Richard B. Mailman, Ph.D.
Professor of Psychiatry, Pharmacology, Neurology, and Medicinal
Chemistry
University of North Carolina School of Medicine
Chapel Hill, NC, USA