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

Wall, Mark J.; Hill, Emily; Huckstepp, Robert; Barkan, Kerry; Deganutti, Giuseppe; Leuenberger, Michele; Preti, Barbara; Winfield, Ian; Carvalho, Sabrina; Suchankova, Anna; Wei, Haifeng; Safitri, Dewi; Huang, Xianglin; Imlach, Wendy; La Mache, Circe; Dean, Eve; Hume, Cherise; Hayward, Stephanie; Oliver, Jess; Zhao, Fei-Yue; ... (27 April 2022). Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression (bioRxiv). Cold Spring Harbor Laboratory 10.1101/2020.04.04.023945

	Text 2020.04.04.023945v4.full.pdf - Published Version Restricted to registered users only Available under License Publisher holds Copyright. Download (6MB)
	Text 2020 Wall BioRxiv v3.pdf - Published Version Restricted to registered users only Available under License Publisher holds Copyright. Download (7MB)
Preview	Text 2024.01.22.576650v1.full.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (5MB) | Preview

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, 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.
Short summary: We describe the selective activation of an adenosine A1 receptor-mediated intracellular pathway that provides potent analgesia in the absence of sedation or cardiorespiratory depression, paving the way for novel medicines based on the far-reaching concept of selective Gα agonism.

Interest & Impact

Downloads

36 since deposited on 04 May 2020
8 in the past 12 months

Citations

5 Citations in Web of Science ®
6 Citations in Scopus

Search

in Google Scholar™

Services

Actions (login required)

Edit item

Actions (login required)

Edit item