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Molecular Pharmacology

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OtherPerspective

Functional Selectivity of GPCR Ligand Stereoisomers: New Pharmacological Opportunities

Roland Seifert and Stefan Dove
Molecular Pharmacology January 2009, 75 (1) 13-18; DOI: https://doi.org/10.1124/mol.108.052944
Roland Seifert
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Stefan Dove
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Abstract

It is now well established that any given ligand for a G-protein-couple receptor (GPCR) does not simply possess a single defined efficacy. Rather, a ligand possesses multiple efficacies, depending on the specific down-stream signal transduction pathway analyzed. This diversity may be based on ligand-specific GPCR conformations and is often referred to as “functional selectivity.” It has been known for a century that stereoisomers of catecholamines differ in their potency and, in some systems, also in their efficacy. However, the molecular basis for efficacy differences of GPCR ligand stereoisomers has remained poorly defined. In an elegant study published in this issue of Molecular Pharmacology, Woo et al. (p. 158) show that stereoisomers of the β2-adrenoceptor selective agonist fenoterol differentially activates Gs- and Gi-proteins in native rat cardiomyocytes. This study is so important because it is the first report to show that even the subtle structural differences within a ligand stereoisomer pair are sufficient to discriminate between GPCR conformations with distinct G-protein coupling properties. The study highlights of how important it is to examine the “more active” (eutomer) and the “less active” (distomer) stereoisomer to understand the mechanisms of action and the cellular effects of GPCR ligands. The study by Woo et al. will ignite a renaissance of the analysis of ligand stereoisomers, using sensitive pharmacological and biophysical assays. The available literature supports the notion that meticulous analysis of ligand stereoisomers is a goldmine for understanding mechanisms of GPCR activation, analysis of signal transduction pathways, development of new therapies for important diseases, and drug safety.

Footnotes

  • Supported by the Deutsche Forschungsgemeinschaft (Graduiertenkolleg 760 “Medicinal Chemistry: Molecular Recognition-Ligand-Receptor Interactions” to R.S. and S.D. While working at the University of Kansas (Lawrence, KS), the β2AR work of R.S. was supported by grants 005140Z and 0450120Z from the Heartland Affiliate of the American Heart Association.

  • Please see the related article on page 158.

  • ABBREVIATIONS: GPCR, G-protein-coupled receptor; AR, adrenergic receptor; TM, transmembrane domain; Gi, inhibitory G-protein of adenylyl cyclase; Gs, stimulatory G-protein of adenylyl cyclase; Gq, stimulatory G-protein of phospholipase C.

    • Received October 21, 2008.
    • Accepted October 21, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 75 (1)
Molecular Pharmacology
Vol. 75, Issue 1
1 Jan 2009
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OtherPerspective

Functional Selectivity of GPCR Ligand Stereoisomers: New Pharmacological Opportunities

Roland Seifert and Stefan Dove
Molecular Pharmacology January 1, 2009, 75 (1) 13-18; DOI: https://doi.org/10.1124/mol.108.052944

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OtherPerspective

Functional Selectivity of GPCR Ligand Stereoisomers: New Pharmacological Opportunities

Roland Seifert and Stefan Dove
Molecular Pharmacology January 1, 2009, 75 (1) 13-18; DOI: https://doi.org/10.1124/mol.108.052944
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  • Article
    • Abstract
    • The β2AR, a Dually Gs- and Gi-Coupled GPCR
    • Different Efficacies of GPCR Ligand Stereoisomers
    • Differential Gs- and Gi-Protein Activation by Fenoterol Stereoisomers
    • How Does the β2AR Activate Gi Proteins?
    • Interaction of Fenoterol Stereoisomers with the β2AR at the Molecular Level
    • Some Future Studies
    • Clinical Implications
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