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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Functional Selectivity and Classical Concepts of Quantitative Pharmacology

Jonathan D. Urban, William P. Clarke, Mark von Zastrow, David E. Nichols, Brian Kobilka, Harel Weinstein, Jonathan A. Javitch, Bryan L. Roth, Arthur Christopoulos, Patrick M. Sexton, Keith J. Miller, Michael Spedding and Richard B. Mailman
Journal of Pharmacology and Experimental Therapeutics January 2007, 320 (1) 1-13; DOI: https://doi.org/10.1124/jpet.106.104463
Jonathan D. Urban
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William P. Clarke
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Mark von Zastrow
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David E. Nichols
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Brian Kobilka
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Harel Weinstein
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Jonathan A. Javitch
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Bryan L. Roth
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Arthur Christopoulos
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Patrick M. Sexton
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Keith J. Miller
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Michael Spedding
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Richard B. Mailman
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Abstract

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.

Footnotes

  • Conflicts of interest: Dr Michael Spedding is both chairman for NC-IUPHAR and deputy director of research for Servier. Dr. Keith Miller is an employee of Bristol-Myers Squibb, Inc. Drs. Mailman and Nichols, the University of North Carolina, and Purdue University have a financial interest in BioValve Technologies, the licensee of compounds mentioned in this article. The opinions presented herein are those of the authors, and not those of any other party.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.106.104463.

  • ABBREVIATIONS: 5-HT, serotonin; (R)-2C-B-CB, 1-aminomethyl-3,6-dimethoxy-4-bromobenzocyclobutane; β2AR, β2-adrenergic receptor; AA, arachidonic acid; DAMGO, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin; DHX, dihydrexidine, trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine; DOB, (–)-1–2,5-dimethoxy-4-bromophenyl-2-aminopropane; GIRK, G protein-coupled inward rectifying potassium channel; GPCR, G protein-coupled receptor; GTPγS, guanosine 5′-(γ-thio)triphosphate; HTS, high-throughput screen; IP, inositol phosphates; IP3, inositol 1,4,5-trisphosphate; IUPHAR, International Union of Basic and Clinical Pharmacology; LSD, d-lysergic acid diethylamide; NC-IUPHAR, nomenclature committee of IUPHAR; N-propylDHX, N-n-propyldihydrexidine; PLA, phospholipase A; PLC, phospholipase C; SB 242084, 6-chloro-5-methyl-N-(6-(2-methylpyridin-3-yloxy)pyridin-3-yl)indoline-1-carboxamide; TM, transmembrane helix; NSIAD, nephrogenic syndrome of inappropriate antidiuresis.

    • Received April 11, 2006.
    • Accepted June 23, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Functional Selectivity and Classical Concepts of Quantitative Pharmacology

Jonathan D. Urban, William P. Clarke, Mark von Zastrow, David E. Nichols, Brian Kobilka, Harel Weinstein, Jonathan A. Javitch, Bryan L. Roth, Arthur Christopoulos, Patrick M. Sexton, Keith J. Miller, Michael Spedding and Richard B. Mailman
Journal of Pharmacology and Experimental Therapeutics January 1, 2007, 320 (1) 1-13; DOI: https://doi.org/10.1124/jpet.106.104463

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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Functional Selectivity and Classical Concepts of Quantitative Pharmacology

Jonathan D. Urban, William P. Clarke, Mark von Zastrow, David E. Nichols, Brian Kobilka, Harel Weinstein, Jonathan A. Javitch, Bryan L. Roth, Arthur Christopoulos, Patrick M. Sexton, Keith J. Miller, Michael Spedding and Richard B. Mailman
Journal of Pharmacology and Experimental Therapeutics January 1, 2007, 320 (1) 1-13; DOI: https://doi.org/10.1124/jpet.106.104463
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