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Biased Ligands of G Protein-Coupled Receptors (GPCRs): Structure–Functional Selectivity Relationships (SFSRs) and Therapeutic Potential
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    Biased Ligands of G Protein-Coupled Receptors (GPCRs): Structure–Functional Selectivity Relationships (SFSRs) and Therapeutic Potential
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    • Liang Tan
      Liang Tan
      iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, Pudong District, Shanghai 201210, China
      More by Liang Tan
    • Wenzhong Yan
      Wenzhong Yan
      iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, Pudong District, Shanghai 201210, China
      More by Wenzhong Yan
    • John D. McCorvy*
      John D. McCorvy
      Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 W. Watertown Plank Road, Milwaukee, Wisconsin 53226, United States
      *J.D.M.: phone, +1 414-955-7635; e-mail, [email protected]
    • Jianjun Cheng*
      Jianjun Cheng
      iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, Pudong District, Shanghai 201210, China
      *J.C.: phone, +86 21 20685237; e-mail, [email protected]
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2018, 61, 22, 9841–9878
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    https://doi.org/10.1021/acs.jmedchem.8b00435
    Published June 25, 2018
    Copyright © 2018 American Chemical Society

    Abstract

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    G protein-coupled receptors (GPCRs) signal through both G-protein-dependent and G-protein-independent pathways, and β-arrestin recruitment is the most recognized one of the latter. Biased ligands selective for either pathway are expected to regulate biological functions of GPCRs in a more precise way, therefore providing new drug molecules with superior efficacy and/or reduced side effects. During the past decade, biased ligands have been discovered and developed for many GPCRs, such as the μ opioid receptor, the angiotensin II receptor type 1, the dopamine D2 receptor, and many others. In this Perspective, recent advances in this field are reviewed by discussing the structure–functional selectivity relationships (SFSRs) of GPCR biased ligands and the therapeutic potential of these molecules. Further understanding of the biological functions associated with each signaling pathway and structural basis for biased signaling will facilitate future drug design in this field.

    Copyright © 2018 American Chemical Society

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2018, 61, 22, 9841–9878
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    https://doi.org/10.1021/acs.jmedchem.8b00435
    Published June 25, 2018
    Copyright © 2018 American Chemical Society

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