Class A G protein-coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numerous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, the adverse effects triggered by the available unbiased GPCR modulators, limit their use and therapeutic value. In this context, the elucidation of biased signalling has opened up new pharmacological avenues holding promise for safer therapeutics. Functionally selective ligands favour receptor conformations facilitating the recruitment of specific effectors and the modulation of the associated pathways. This review surveys the current drug discovery landscape of GPCR-biased modulators with a focus on recent advances. Understanding the biological effects of this preferential coupling is at different stages depending on the Class A GPCR family. Therefore, with a focus on individual GPCR families, we present a compilation of the functionally selective modulators reported over the past few years. In doing so, we dissect their therapeutic relevance, molecular determinants and potential clinical applications. LINKED ARTICLES: This article is part of a themed issue Complexity of GPCR Modulation and Signaling (ERNST). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.14/issuetoc.

Celtarys Research S L Santiago de Compostela Spain

Center for Research in Biological Chemistry and Molecular Materials University of Santiago de Compostela Santiago de Compostela Spain

CiberNed Network Center for Neurodegenerative Diseases National Spanish Health Institute Carlos 3 Madrid Spain

Department of Biochemistry and Physiology Faculty of Pharmacy and Food Science Universitat de Barcelona Barcelona Spain

Department of Pharmacology and Cancer Biology Duke University School of Medicine Durham North Carolina USA

Department of Physiology and Pharmacology Karolinska Institutet Stockholm Sweden

Heinrich Heine University Düsseldorf Institut fuer Pharmazeutische und Medizinische Chemie Duesseldorf Germany

Institute for Pharmaceutical and Medicinal Chemistry University of Münster Münster Germany

Institute of Biomedicine Universitat de Barcelona Barcelona Spain

Institute of Physiology Czech Academy of Sciences Prague Czech Republic

Instituto de Química Médica Consejo Superior de Investigaciones Científicas Madrid Spain

Laboratory of Medicinal Chemistry Faculty of Pharmacy and Food Sciences Universitat de Barcelona Barcelona Spain

Laboratory of Molecular Pharmacology Department of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Medicinal Chemistry Research Group and National Drug Discovery and Development Laboratory Research Centre for Natural Sciences Budapest Hungary

Molecular Neurobiology Laboratory Department of Biochemistry and Molecular Biology Universitat de Barcelona Barcelona Spain

School of Chemistry Universitat de Barcelona Barcelona Spain

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