The researchers discovered that the compound benzyloxy-cyclopentyladenosine was a potent painkiller in test model systems.
A promising new non-opioid painkiller (analgesic) has been discovered, with potentially fewer side effects than other potent painkillers.
A team of researchers led by scientists from the University of Warwick’s School of Life Sciences has analyzed a compound known as BnOCPA (benzyloxy-cyclopentyladenosine) which was discovered to be a powerful and selective analgesic that is non-addictive in test model systems. BnOCPA also has a unique mode of action, which could provide a new path for the creation of analgesic drugs.
The study, conducted by the Warwick team in collaboration with researchers from the University of Bern, University of Cambridge, Coventry University, Monash University, and industrial organizations, was recently published in in the journal Nature Communications.
In the UK, between a third and a half of the population report having chronic pain that is either moderately or severely disabling. Such pain negatively affects the quality of life, and many of the often prescribed painkillers have side effects. Opioids, such as morphine and oxycodone, can cause addiction and are dangerous when used in excess. There is thus an unmet need for new, powerful painkillers.
Many drug works by activating adapter molecules known as G proteins on the cell surface. The activation of G proteins can cause a variety of cellular effects. Because just one kind of G protein is activated by BnOCPA, its actions are very selective, minimizing the possibility of negative side effects.
Dr. Mark Wall, from the School of Life Sciences at the University of Warwick, who led the research stated: “The selectivity and potency of BnOCPA make it truly unique and we hope that with further research it will be possible to generate potent painkillers to help patients cope with chronic pain.”
Professor Bruno Frenguelli, principal investigator on the project, from the University of Warwick’s School of Life Sciences, added: “This is a fantastic example of serendipity in science. We had no expectations that BnOCPA would behave any differently from other molecules in its class, but the more we looked into BnOCPA we discovered properties that had never been seen before, and which may open up new areas of medicinal chemistry.”
Professor Graham Ladds, co-principal investigator on the project, from the University of Cambridge, said: “This is an amazing story looking at agonist bias for a GPCR. Not only does BnOCPA have the potential to be a new type of painkiller, but it has shown us a new method for targeting other GPCRs in drug discovery.”
Reference: “Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression” by 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 La 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, 18 July 2022, Nature Communications.
DOI: 10.1038/s41467-022-31652-2
