A biased adenosine A1R agonist confers analgesia without cardiorespiratory depression

Wall, Mark J.; Hill, Emily; Huckstepp, Robert; Barkan, Kerry; Deganutti, Giuseppe; Leuenberger, Michele; Preti, Barbara; Winfield, Ian; Wei, Haifeng; Imlach, Wendy; Dean, Eve; Hume, Cherise; Hayward, Stephanie; Oliver, Jess; Zhao, Fei-Yue; Spanswick, David; Reynolds, Christopher A.; Lochner, Martin; Ladds, Graham and Frenguelli, Bruno G. (16 June 2020). A biased adenosine A1R agonist confers analgesia without cardiorespiratory depression bioRxiv 10.1101/2020.04.04.023945

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The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple Gα subunits. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A1 receptors (A1Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A1R-selective agonist, BnOCPA, is a potent and powerful analgesic but does not cause sedation, bradycardia, hypotension or respiratory depression. This unprecedented discrimination between native A1Rs arises from BnOCPA's unique and highly biased activation of Gob among the six Gαi/o subtypes, and in the absence of β-arrestin recruitment. BnOCPA thus demonstrates a hitherto unknown Gα-selective activation of the native A1R, sheds new light on the fundamentals of GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of biased agonism.

Item Type:

Working Paper

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Leuenberger, Michele; Preti, Barbara and Lochner, Martin

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health
500 Science > 540 Chemistry

Publisher:

bioRxiv

Funders:

[4] Swiss National Science Foundation
[UNSPECIFIED] BBSRC
[UNSPECIFIED] Leverhulme Trust
[UNSPECIFIED] MRC

Language:

English

Submitter:

Martin Lochner

Date Deposited:

04 May 2020 16:49

Last Modified:

19 Jun 2020 10:09

Publisher DOI:

10.1101/2020.04.04.023945

BORIS DOI:

10.7892/boris.143509

URI:

https://boris.unibe.ch/id/eprint/143509

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