NEW HOT PAPERS

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.

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