TY - JOUR
T1 - Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression
AU - Wall, Mark J.
AU - Hill, Emily
AU - Huckstepp, Robert
AU - Barkan, Kerry
AU - Deganutti, Giuseppe
AU - Leuenberger, Michele
AU - Preti, Barbara
AU - Winfield, Ian
AU - Carvalho, Sabrina
AU - Suchankova, Anna
AU - Wei, Haifeng
AU - Safitri, Dewi
AU - Huang, Xianglin
AU - Imlach, Wendy
AU - Mache, Circe La
AU - Dean, Eve
AU - Hume, Cherise
AU - Hayward, Stephanie
AU - Oliver, Jess
AU - Zhao, Fei-Yue
AU - Spanswick, David
AU - Reynolds, Christopher A.
AU - Lochner, Martin
AU - Ladds, Graham
AU - Frenguelli, Bruno G.
N1 - This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
PY - 2022/7/18
Y1 - 2022/7/18
N2 - 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 A
1 receptors (A
1Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A
1R-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 A
1Rs 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 A
1R, 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.
AB - 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 A
1 receptors (A
1Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A
1R-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 A
1Rs 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 A
1R, 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.
KW - General Biochemistry, Genetics and Molecular Biology
KW - General Chemistry
KW - General Physics and Astronomy
KW - Multidisciplinary
UR - http://www.scopus.com/inward/record.url?scp=85134406622&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-31652-2
DO - 10.1038/s41467-022-31652-2
M3 - Article
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4150
ER -