Functional selectivity and classical concepts of quantitative pharmacology Public Deposited

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  • Weinstein, Harel
    • Other Affiliation: Department of Physiology and Biophysics, and Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, NY
  • Christopoulos, Arthur
    • Other Affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia
  • Javitch, Jonathan A.
    • Other Affiliation: Center for Molecular Recognition, and Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY
  • Spedding, Michael
    • Other Affiliation: Institute de Recherches Servier, Suresnes, France
  • Nichols, David E.
    • Other Affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, IN
  • Urban, Jonathan D.
    • Affiliation: School of Medicine, Curriculum in Toxicology
  • Clarke, William P.
    • Other Affiliation: Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX
  • Sexton, Patrick M.
    • Other Affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia
  • Mailman, Richard B.
    • Affiliation: School of Medicine, Department of Pharmacology, Department of Neurology, Eshelman School of Pharmacy, Department of Psychiatry, Curriculum in Toxicology, Division of Chemical Biology and Medicinal Chemistry
  • Kobilka, Brian
    • Other Affiliation: Department of Molecular and Cellular Physiology, Stanford University, Palo Alto, CA
  • Miller, Keith J.
    • Other Affiliation: Obesity Department, Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, NJ
  • von Zastrow, Mark
    • Other Affiliation: Departments of Psychiatry and Cellular and Molecular Pharmacology, University of California, San Francisco, CA
  • Roth, Bryan
    • ORCID:
    • Affiliation: School of Medicine, Department of Pharmacology, Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Department of Psychiatry
  • 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.
Date of publication
  • doi:10.1124/jpet.106.104463
  • 2-s2.0-33845903110
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Resource type
  • Journal Item
Rights statement
  • In Copyright
Journal title
  • Journal of Pharmacology and Experimental Therapeutics
Journal volume
  • 320
Journal issue
  • 1
Page start
  • 1
Page end
  • 13
  • English
  • Postprint
  • 0022-3565

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