Scientists develop a new non-opioid pain killer with fewer side effects

A team of scientists, co-led by researchers from the School of Life Sciences, University of Warwick, has investigated a compound called BnOCPA (benzyloxy-cyclopentyladenosine), found to be a potent and selective analgesic which is non-addictive in test model systems. BnOCPA also has a unique mode of action and potentially opens a new pipeline for the development of new analgesic drugs.

The research by the team at Warwick, together with colleagues at the University of Cambridge, University of Bern, Monash University, Coventry University and industrial collaborators, is published in Nature Communications in a paper entitled "Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression".

In the UK between one third and one half of the population report moderately to severely disabling chronic pain. Such pain has a negative impact on quality of life and many of the commonly used pain killers produce side effects. Opioid drugs, such as morphine and oxycodone, can lead to addiction and are dangerous in overdose. There is therefore an unmet need for new and potent pain killing drugs.

Many drugs act via proteins on the surface of cell surfaces that activate adapter molecules called G proteins. The activation of G proteins can lead to many cellular effects. BnOCPA is unique in that it only activates one type of G protein, leading to very selective effects and thus reducing potential side effects.

Dr Mark Wall, from the School of Life Sciences at the University of Warwick, who led the research said: "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, said: "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:

Wall, M.J., Hill, E., Huckstepp, R. et al. Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression. Nat Commun 13, 4150 (2022). https://doi.org/10.1038/s41467-022-31652-2