RT Journal Article
SR Electronic
T1 Functional Selectivity and Classical Concepts of Quantitative Pharmacology
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1
OP 13
DO 10.1124/jpet.106.104463
VO 320
IS 1
A1 Jonathan D. Urban
A1 William P. Clarke
A1 Mark von Zastrow
A1 David E. Nichols
A1 Brian Kobilka
A1 Harel Weinstein
A1 Jonathan A. Javitch
A1 Bryan L. Roth
A1 Arthur Christopoulos
A1 Patrick M. Sexton
A1 Keith J. Miller
A1 Michael Spedding
A1 Richard B. Mailman
YR 2007
UL http://jpet.aspetjournals.org/content/320/1/1.abstract
AB The concept of intrinsic efficacy has been enshrined in pharmacology for half of a century, yet recent data have revealed that many ligands can differentially activate signaling pathways mediated via a single G protein-coupled receptor in a manner that challenges the traditional definition of intrinsic efficacy. Some terms for this phenomenon include functional selectivity, agonist-directed trafficking, and biased agonism. At the extreme, functionally selective ligands may be both agonists and antagonists at different functions mediated by the same receptor. Data illustrating this phenomenon are presented from serotonin, opioid, dopamine, vasopressin, and adrenergic receptor systems. A variety of mechanisms may influence this apparently ubiquitous phenomenon. It may be initiated by differences in ligand-induced intermediate conformational states, as shown for the β2-adrenergic receptor. Subsequent mechanisms that may play a role include diversity of G proteins, scaffolding and signaling partners, and receptor oligomers. Clearly, expanded research is needed to elucidate the proximal (e.g., how functionally selective ligands cause conformational changes that initiate differential signaling), intermediate (mechanisms that translate conformation changes into differential signaling), and distal mechanisms (differential effects on target tissue or organism). Besides the heuristically interesting nature of functional selectivity, there is a clear impact on drug discovery, because this mechanism raises the possibility of selecting or designing novel ligands that differentially activate only a subset of functions of a single receptor, thereby optimizing therapeutic action. It also may be timely to revise classic concepts in quantitative pharmacology and relevant pharmacological conventions to incorporate these new concepts. The American Society for Pharmacology and Experimental Therapeutics