Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression

Mark J. Wall (), Emily Hill, Robert Huckstepp, Kerry Barkan, Giuseppe Deganutti, Michele Leuenberger, Barbara Preti, Ian Winfield, Sabrina Carvalho, Anna Suchankova, Haifeng Wei, Dewi Safitri, Xianglin Huang, Wendy Imlach, Circe Mache, Eve Dean, Cherise Hume, Stephanie Hayward, Jess Oliver, Fei-Yue Zhao, David Spanswick, Christopher A. Reynolds, Martin Lochner, Graham Ladds () and Bruno G. Frenguelli ()
Additional contact information
Mark J. Wall: University of Warwick
Emily Hill: University of Warwick
Robert Huckstepp: University of Warwick
Kerry Barkan: University of Cambridge
Giuseppe Deganutti: Coventry University
Michele Leuenberger: University of Bern
Barbara Preti: University of Bern
Ian Winfield: University of Cambridge
Sabrina Carvalho: University of Cambridge
Anna Suchankova: University of Cambridge
Haifeng Wei: NeuroSolutions Ltd
Dewi Safitri: University of Cambridge
Xianglin Huang: University of Cambridge
Wendy Imlach: Monash University
Circe Mache: University of Warwick
Eve Dean: University of Warwick
Cherise Hume: University of Warwick
Stephanie Hayward: University of Warwick
Jess Oliver: University of Warwick
Fei-Yue Zhao: NeuroSolutions Ltd
David Spanswick: NeuroSolutions Ltd
Christopher A. Reynolds: Coventry University
Martin Lochner: University of Bern
Graham Ladds: University of Cambridge
Bruno G. Frenguelli: University of Warwick

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple intracellular 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, benzyloxy-cyclopentyladenosine (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 selective activation of Gob among the six Gαi/o subtypes, and in the absence of β-arrestin recruitment. BnOCPA thus demonstrates a highly-specific Gα-selective activation of the native A1R, sheds new light on GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of selective Gα agonism.

Date: 2022
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DOI: 10.1038/s41467-022-31652-2

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