A biased adenosine A1R agonist elicits analgesia without cardiorespiratory depression

Mark J. Wall, Emily Hill, Robert Huckstepp, Kerry Barkan, Giuseppe Deganutti, Michele Leuenberger, Barbara Preti, Ian Winfield, Haifeng Wei, Wendy Imlach, Eve Dean, Cherise Hume, Stephanie Hayward, Jess Oliver, Fei-Yue Zhao, David Spanswick, Christopher A. Reynolds, Martin Lochner, Graham Ladds, Bruno G. Frenguelli

Research output: Other contribution

Abstract

The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple signalling pathways. 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 exquisitely 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.
Original languageEnglish
TypePre-Print
Media of outputOnline
PublisherbioRxiv
DOIs
Publication statusPublished - 5 Apr 2020
Externally publishedYes

Fingerprint Dive into the research topics of 'A biased adenosine A1R agonist elicits analgesia without cardiorespiratory depression'. Together they form a unique fingerprint.

  • Cite this

    Wall, M. J., Hill, E., Huckstepp, R., Barkan, K., Deganutti, G., Leuenberger, M., ... Frenguelli, B. G. (2020, Apr 5). A biased adenosine A1R agonist elicits analgesia without cardiorespiratory depression. bioRxiv. https://doi.org/10.1101/2020.04.04.023945