Ga-selective adenosine A1 receptor agonists as novel analgesics devoid of cardiorespiratory depression

Chronic pain, defined as continuous, frequent, or recurring pain lasting more than three months, affects up to 50% of the UK population. Such pain is often not adequately treated with available painkillers, and sufferers may end up having to take powerful drugs, such as opioids, which have undesirable and harmful side effects including nausea, constipation, tolerance, dependence and abuse potential. There is therefore a great need for new types of painkilling drugs. One painkilling system in the body that does not involve opioids is the system targeted by a naturally-occurring molecule called adenosine. Adenosine acts upon its receptors on the surface of cells to elicit various physiological responses inside those cells and hence in the tissues and organs that are made up of those cells. The activation of one of these receptors, the A1 receptor (A1R), has long been known to reduce the sensation of pain, but also to have unwanted effects on heart rate, blood pressure and respiration. For these reasons, previous attempts to develop painkilling drugs that activate the A1R have failed. We have recently discovered that a molecule called BnOCPA, which activates the A1R, is a powerful painkiller. However, it does so without causing effects on heart rate, blood pressure or respiration, and, in addition, does not cause sedation. This observation is unprecedented, and we believe that this is due to BnOCPA only activating one of the six possible proteins inside the cell through which the A1R normally acts. The fact that the protein that BnOCPA activates is not found in the heart likely explains the lack of cardiovascular effects of BnOCPA. In this proposal we wish to do three things: i) understand, at the level of spinal cord pain pathways, how BnOCPA acts to induce analgesia; ii) determine if BnOCPA is as effective in a model of chronic inflammatory pain of the type seen in arthritis, as it is in a model of neuropathic pain, which can occur after nerve injury or in certain diseases, and iii) establish whether more potent variants of the chemical structure of BnOCPA offer the same analgesic properties devoid of any effects on the cardiorespiratory system. This will give us insight into the chemical fingerprint responsible for the peculiar action of BnOCPA, and may lead to the development of more effective painkilling drugs with reduced risk of side effects. To conduct this study, experts in pain and the workings of the nervous system at Warwick University will team up with a chemist in Switzerland who makes BnOCPA and its variants, a team at the University of Cambridge who study the interaction between adenosine receptors and the proteins they activate inside cells, and colleagues at the University of Coventry who will use sophisticated computer models to interrogate at the atomic level the interactions between molecules, receptor and proteins. This comprehensive series of studies will generate great insights into the painkilling mechanism of this highly unusual molecule, identify additional types of pain in which it may be effective, and reveal new compounds capable of eliciting analgesia without effects on the cardiovascular or respiratory systems. Such studies are necessary if we are to develop new painkillers to reduce both the burden of pain for patients and the risks associated with the use of opioid analgesics.