title: The role of kinetic context in apparent biased agonism at GPCRs.
abstract: Biased agonism describes the ability of ligands to stabilize different conformations of a GPCR linked to distinct functional outcomes and offers the prospect of designing pathway-specific drugs that avoid on-target side effects. This mechanism is usually inferred from pharmacological data with the assumption that the confounding influences of observational (that is, assay dependent) and system (that is, cell background dependent) bias are excluded by experimental design and analysis. Here we reveal that 'kinetic context', as determined by ligand-binding kinetics and the temporal pattern of receptor-signalling processes, can have a profound influence on the apparent bias of a series of agonists for the dopamine D2 receptor and can even lead to reversals in the direction of bias. We propose that kinetic context must be acknowledged in the design and interpretation of studies of biased agonism.
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Carmen
authors.initials: C
authors.lastname: Klein Herenbrink
authors.affiliation: Cell Signalling Research Group, School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Sykes
authors.affiliation: Departments of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.|Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Prashant
authors.initials: P
authors.lastname: Donthamsetti
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Canals
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Coudrat
authors.affiliation: Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Shonberg
authors.affiliation: Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scammells
authors.affiliation: Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Ben
authors.initials: B
authors.lastname: Capuano
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Patrick M
authors.identifier: http://orcid.org/0000-0001-8902-2473
authors.initials: PM
authors.lastname: Sexton
authors.affiliation: Cell Signalling Research Group, School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Charlton
authors.affiliation: Departments of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.|Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.|Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Javitch
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: J Robert
authors.initials: JR
authors.lastname: Lane
mesh_terms: D000818:Animals; D000068180:Aripiprazole / Q000493:pharmacokinetics; D016466:CHO Cells; D003412:Cricetulus; D004298:Dopamine / Q000493:pharmacokinetics; D018491:Dopamine Agonists / Q000493:pharmacokinetics*; D007211:Indoles / Q000493:pharmacokinetics; D007700:Kinetics; D008024:Ligands; D010879:Piperazines / Q000493:pharmacokinetics; D010880:Piperidines / Q000493:pharmacokinetics; D025341:Principal Component Analysis; D055550:Protein Stability; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism
chemical_list: D018491:Dopamine Agonists; D007211:Indoles; D008024:Ligands; D010879:Piperazines; D010880:Piperidines; D017448:Receptors, Dopamine D2; C046649:ropinirole; D000068180:Aripiprazole; C026539:preclamol; C533287:cariprazine; D004298:Dopamine