Primary supervisor: Professor Bruno Frenguelli & Dr Mark Wall, School of Life Sciences
Non-academic partner: Neurosolutions Ltd
Project Title: Identification of novel purine-based analgesics
Chronic pain is a major burden on sufferers, their families and society in general. Whilst there are numerous pain medications and therapies available for chronic pain, the pain of many sufferers is insufficiently alleviated due to lack of efficacy of the treatment or due to unacceptable side effects. There is thus a great unmet need for the development of novel analgesics.
The purines, ATP and adenosine, have been known for many years to have an important role in the sensation and transmission of pain impulses in the nervous system: ATP provokes the feeling of pain, and antagonists of ATP receptors have been proposed as analgesics, whilst adenosine is a naturally-occurring analgesic. Attempts to harness the anti-nociceptive (pain killing) properties of adenosine are hampered by the wide range of cellular actions of adenosine that are mediated by the four different adenosine receptors and the many and varied intracellular signalling cascades they initiate.
What is required to circumvent this rate-limiting step are compounds that not only show selectivity for a particular adenosine receptor subtype, but which also possess the ability to selectively activate intracellular signalling cascades. Compounds exhibiting such selective agonism would activate the desired actions of adenosine receptors (analgesia) in the absence of undesired side effects (eg bradycardia or hypotension).
In a collaboration with colleagues at the Universities of Cambridge, Bern, Coventry and Essex (Knight et al., 2016; Deganutti et al 2021) we believe we have identified just such a class of compounds. The proposed PhD project would extend these cellular and molecular studies into models of pain. To do this, we will use a multidisciplinary approach, combining novel organic synthetic chemistry, cellular assays of receptor pharmacology and G protein-coupling, in vivo and in vitro electrophysiology, and behavioural analyses in preclinical models of chronic pain.
- Knight A, Hemmings JL, Winfield I, Leuenberger M, Frattini E, Frenguelli BG, Dowell SJ, Lochner M, Ladds G. Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity. J Med Chem. 2016 59:947-64. doi: 10.1021/acs.jmedchem.5b01402
- Deganutti G, Barkan K, Preti B, Leuenberger M, Wall M, Frenguelli BG, Lochner M, Ladds G, Reynolds CA. Deciphering the Agonist Binding Mechanism to the Adenosine A1 Receptor. ACS Pharmacol Transl Sci. 2021 4:314-326. doi: 10.1021/acsptsci.0c00195