Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery

Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018

(2020) Olivier J. Wouters et al.   JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION

The GPCR accessory protein MRAP2 regulates both biased signaling and constitutive activity of the ghrelin receptor GHSR1a

(2020) Alix A. J. Rouault et al.   Science Signaling

Dawn of a New RAMPage

(2020) D. Stephen Serafin et al.   TRENDS IN PHARMACOLOGICAL SCIENCES

Enhancing the Signaling of GPCRs via Orthosteric Ions

(2020) H. C. Stephen Chan et al.   ACS Central Science

β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors

(2020) Lauren M. Slosky et al.   CELL

TRUPATH, an open-source biosensor platform for interrogating the GPCR transducerome

(2020) Reid H. J. Olsen et al.   Nature Chemical Biology

Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists

(2020) Alexander Gillis et al.   Science Signaling

Combining Allosteric and Orthosteric Drugs to Overcome Drug Resistance

(2020) Duan Ni et al.   TRENDS IN PHARMACOLOGICAL SCIENCES

Biased Signaling and Allosteric Modulation at the FSHR

(2019) Flavie Landomiel et al.   Frontiers in Endocrinology

Allosteric Modulator Discovery: From Serendipity to Structure-Based Design

(2019) Shaoyong Lu et al.   JOURNAL OF MEDICINAL CHEMISTRY

The δ‐opioid receptor positive allosteric modulator BMS 986187 is a G‐protein‐biased allosteric agonist

(2019) M. Alexander Stanczyk et al.   BRITISH JOURNAL OF PHARMACOLOGY

Trends in clinical success rates and therapeutic focus

(2019) Helen Dowden et al.   NATURE REVIEWS DRUG DISCOVERY

Illuminating G-Protein-Coupling Selectivity of GPCRs

(2019) Asuka Inoue et al.   CELL

Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators

(2019) Anthony B. Pinkerton et al.   JOURNAL OF MEDICINAL CHEMISTRY

G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs?

(2018) Krishna Sriram et al.   MOLECULAR PHARMACOLOGY

Biased signalling: from simple switches to allosteric microprocessors

(2018) Jeffrey S. Smith et al.   NATURE REVIEWS DRUG DISCOVERY

A Genetically Encoded Biosensor Reveals Location Bias of Opioid Drug Action

(2018) Miriam Stoeber et al.   NEURON

PAM-Antagonists: A Better Way to Block Pathological Receptor Signaling?

(2018) Terry Kenakin et al.   TRENDS IN PHARMACOLOGICAL SCIENCES

Fenoprofen -- an old drug rediscovered as a biased allosteric enhancer for melanocortin receptors

(2018) Xiao-Chen Yuan et al.   ACS Chemical Neuroscience

Toward an understanding of the structural basis of allostery in muscarinic acetylcholine receptors

(2018) Wessel A.C. Burger et al.   JOURNAL OF GENERAL PHYSIOLOGY

Pepducin-mediated cardioprotection via β-arrestin-biased β2-adrenergic receptor-specific signaling

(2018) Laurel A. Grisanti et al.   Theranostics

Pyrimidinyl Biphenylureas Act as Allosteric Modulators to Activate Cannabinoid Receptor 1 and Initiate β-Arrestin–Dependent Responses

(2018) Caitlin A. D. Jagla et al.   MOLECULAR PHARMACOLOGY

Pyrimidinyl Biphenylureas: Identification of New Lead Compounds as Allosteric Modulators of the Cannabinoid Receptor CB1

(2017) Leepakshi Khurana et al.   JOURNAL OF MEDICINAL CHEMISTRY

Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs

(2017) John D McCorvy et al.   Nature Chemical Biology

Trends in GPCR drug discovery: new agents, targets and indications

(2017) Alexander S. Hauser et al.   NATURE REVIEWS DRUG DISCOVERY

Applying Structure-Based Drug Design Approaches to Allosteric Modulators of GPCRs

(2017) Miles Congreve et al.   TRENDS IN PHARMACOLOGICAL SCIENCES

Temporal Bias: Time-Encoded Dynamic GPCR Signaling

(2017) Manuel Grundmann et al.   TRENDS IN PHARMACOLOGICAL SCIENCES

A Practical Guide to Approaching Biased Agonism at G Protein Coupled Receptors

(2017) Jaimee Gundry et al.   Frontiers in Neuroscience

G protein stoichiometry dictates biased agonism through distinct receptor-G protein partitioning

(2017) Lauriane Onfroy et al.   Scientific Reports

A single extracellular amino acid in Free Fatty Acid Receptor 2 defines antagonist species selectivity and G protein selection bias

(2017) Eugenia Sergeev et al.   Scientific Reports

ML314: A Biased Neurotensin Receptor Ligand for Methamphetamine Abuse

(2016) Larry S. Barak et al.   ACS Chemical Biology

From biased signalling to polypharmacology: unlocking unique intracellular signalling using pepducins

(2016) Richard Carr et al.   BIOCHEMICAL SOCIETY TRANSACTIONS

Towards a structural understanding of allosteric drugs at the human calcium-sensing receptor

(2016) Katie Leach et al.   CELL RESEARCH

Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3

(2016) Trinidad Montero-Melendez et al.   CELLULAR AND MOLECULAR LIFE SCIENCES

A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias

(2016) Daniele Bolognini et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

A comprehensive map of molecular drug targets

(2016) Rita Santos et al.   NATURE REVIEWS DRUG DISCOVERY

β-arrestin–biased signaling through the β2-adrenergic receptor promotes cardiomyocyte contraction

(2016) Richard Carr et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Distinct cortical and striatal actions of a β-arrestin–biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties

(2016) Nikhil M. Urs et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

The role of kinetic context in apparent biased agonism at GPCRs

(2016) Carmen Klein Herenbrink et al.   Nature Communications

AZD8797 is an allosteric non-competitive modulator of the human CX3CR1 receptor

(2015) L. Cederblad et al.   BIOCHEMICAL JOURNAL

Novel Allosteric Modulators of G Protein-coupled Receptors

(2015) Patrick R. Gentry et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Discovery, Synthesis, and Molecular Pharmacology of Selective Positive Allosteric Modulators of the δ-Opioid Receptor

(2015) Neil T. Burford et al.   JOURNAL OF MEDICINAL CHEMISTRY

Studying the binding interactions of allosteric agonists and antagonists of the CXCR4 receptor

(2015) Jesús M. Planesas et al.   JOURNAL OF MOLECULAR GRAPHICS & MODELLING

Operational models of allosteric modulation: caution is needed

(2015) Jesús Giraldo   TRENDS IN PHARMACOLOGICAL SCIENCES

Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics

(2014) A E Cook et al.   BRITISH JOURNAL OF PHARMACOLOGY

Development and Characterization of Pepducins as Gs-biased Allosteric Agonists

(2014) Richard Carr et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Allosteric Modulation of β-Arrestin-biased Angiotensin II Type 1 Receptor Signaling by Membrane Stretch

(2014) Wei Tang et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Minireview: More Than Just a Hammer: Ligand “Bias” and Pharmaceutical Discovery

(2014) Louis M. Luttrell   MOLECULAR ENDOCRINOLOGY

Molecular control of δ-opioid receptor signalling

(2014) Gustavo Fenalti et al.   NATURE

Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders

(2014) P. Jeffrey Conn et al.   NATURE REVIEWS DRUG DISCOVERY

Allosteric and Biased G Protein-Coupled Receptor Signaling Regulation: Potentials for New Therapeutics

(2014) Etienne Khoury et al.   Frontiers in Endocrinology

Mechanistic analysis of the function of agonists and allosteric modulators: reconciling two-state and operational models

(2013) David Roche et al.   BRITISH JOURNAL OF PHARMACOLOGY

Recent developments in biased agonism

(2013) James W Wisler et al.   CURRENT OPINION IN CELL BIOLOGY

Distinct Roles of β-Arrestin 1 and β-Arrestin 2 in ORG27569-induced Biased Signaling and Internalization of the Cannabinoid Receptor 1 (CB1)

(2013) Kwang H. Ahn et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Polypharmacology – Foe or Friend?

(2013) Jens-Uwe Peters   JOURNAL OF MEDICINAL CHEMISTRY

Signalling bias in new drug discovery: detection, quantification and therapeutic impact

(2013) Terry Kenakin et al.   NATURE REVIEWS DRUG DISCOVERY

Pepducin targeting the C-X-C chemokine receptor type 4 acts as a biased agonist favoring activation of the inhibitory G protein

(2013) J. Quoyer et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Discovery of ML314, a Brain Penetrant Nonpeptidic β-Arrestin Biased Agonist of the Neurotensin NTR1 Receptor

(2013) Satyamaheshwar Peddibhotla et al.   ACS Medicinal Chemistry Letters

GPCR heterodimers: asymmetries in ligand binding and signalling output offer new targets for drug discovery

(2012) Eugénie Goupil et al.   BRITISH JOURNAL OF PHARMACOLOGY

Allosteric Modulator ORG27569 Induces CB1 Cannabinoid Receptor High Affinity Agonist Binding State, Receptor Internalization, and GiProtein-independent ERK1/2 Kinase Activation

(2012) Kwang H. Ahn et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

TGFα shedding assay: an accurate and versatile method for detecting GPCR activation

(2012) Asuka Inoue et al.   NATURE METHODS

Structure-based drug screening for G-protein-coupled receptors

(2012) Brian K. Shoichet et al.   TRENDS IN PHARMACOLOGICAL SCIENCES

A Novel Biased Allosteric Compound Inhibitor of Parturition Selectively Impedes the Prostaglandin F2α-mediated Rho/ROCK Signaling Pathway

(2010) Eugénie Goupil et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Teaching old receptors new tricks: biasing seven-transmembrane receptors

(2010) Sudarshan Rajagopal et al.   NATURE REVIEWS DRUG DISCOVERY

Allostery at G Protein-Coupled Receptor Homo- and Heteromers: Uncharted Pharmacological Landscapes

(2010) N. J. Smith et al.   PHARMACOLOGICAL REVIEWS

Guide to Receptors and Channels (GRAC), 4th edition

(2009)   BRITISH JOURNAL OF PHARMACOLOGY

Synthesis and Structure-Activity Relationships of Allosteric Potentiators of the M4Muscarinic Acetylcholine Receptor

(2009) J. Phillip Kennedy et al.   ChemMedChem

Receptor Activity-Modifying Proteins Differentially Modulate the G Protein-Coupling Efficiency of Amylin Receptors

(2008) Maria Morfis et al.   ENDOCRINOLOGY

Structural diversity of G protein-coupled receptors and significance for drug discovery

(2008) Malin C. Lagerström et al.   NATURE REVIEWS DRUG DISCOVERY

Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders

(2008) P. Jeffrey Conn et al.   NATURE REVIEWS DRUG DISCOVERY