Research Impact


Cloning of the P2X3 receptor leads to the development of new painkillers

12 December 2014


In 1995, collaboration at UCL led to the first cloning of the P2X3 receptor, which mediates pain information. P2X3 antagonists are now being developed as novel analgesics. As well as clinical benefits, these drug developments are associated with substantial economic and commercial benefits.

Adenosine 5'-triphosphate (ATP) was originally considered an exclusively intracellular energy source. Against consensus opinion, Professor Geoffrey Burnstock (UCL Cell & Developmental Biology) pioneered the notion that ATP and its derivatives can also act as extracellular messengers. Several decades of research have proven his groundbreaking theory correct. Today, the research he founded on purinergic signalling is a vast and expanding field of biomedical study. We now know that such signalling occurs in many cell types throughout the body, including neurons, smooth muscle cells, epithelial cells, erythrocytes, immune cells and sperm.

Professor Burnstock was the first to define three distinct classes of purinergic receptor: P1, P2Y and P2X receptors. Important roles for these receptor types have already been identified in development (from cell cycling to migration), normal physiology (from pain sensation to bladder contraction) and pathology (from arthritis to cancer).

His seminal research on ATP has helped ensure his influence on understanding and practice among both industry and healthcare professionals. He has provided consultancy or research support to more than 35 pharmaceutical companies and collaborated with clinicians around the world on over 70 projects. These have included work on skin inflammation, motor neuron disease, diabetes, traumatic shock, liver and colorectal tumours, bladder incontinence, vitamin E deficiency, hypertension, and pancreatic, bladder and prostate cancer. Professor Burnstock is currently the Senior Advisor for the Neuroallianz established by the German government to link basic science, clinical science and the drug industry.

More specific benefits of Professor Burnstock's work on purinergic signalling include the development of P2X3 antagonists as novel analgesics. This development has its origins in a 1995 collaboration with Professor John Wood, Head of the UCL Molecular Nociception Group, which led to the first cloning of the P2X3 ion channel receptor located on nociceptive sensory nerves. In 1999, Professor Burnstock proposed that pain in visceral organs was catalysed by the release of ATP which, he suggested, acts on the P2X3 receptors on subepithelial sensory nerve endings to send messages to the brain. Supporting evidence for this hypothesis in the bladder, ureter and gut was later reported by his lab. In 2000, the lab demonstrated that pain-related behaviour is reduced in P2X3-deficient mice, indicating that P2X3 ion channel receptors do indeed play an important role in signalling pain. These observations have since been influential in the development of novel selective painkillers that might offer new relief to the 270 million people worldwide who suffer from chronic pain.

Despite the huge number of people who could benefit from them, there has been little recent success in advancing truly novel pain relief therapies, and existing therapies (including opioids, antiepileptic drugs and non-steroidal anti-inflammatory drugs) all come with well-documented drawbacks. Unsurprisingly, therefore, the pharmaceutical industry has been much interested in the potential of Professor Burnstock's findings to support the development of new methods of tackling pain, and more than 600 patents are currently held that relate to the P2X3 receptor and pain. Of particular note is the development by Roche (with whom Professor Burnstock was a Consultant and Research Collaborator for over six years) and more recently Afferent Pharmaceuticals (on whose Scientific Advisory Board he is a member) of AF-219, a specific P2X3 receptor antagonist and a promising new analgesic.

Four Phase 1 studies of AF-219 demonstrated that the compound is safe and well tolerated and it is currently in US-based Phase 2 proof-of-concept studies for the treatment of two painful disorders: osteoarthritis, which is the most common form of arthritis, and interstitial cystitis/bladder pain syndrome, which is experienced by 3-7% of women. A UK-based Phase 2 pilot study of AF-219A was completed in 2013 for the treatment of idiopathic chronic cough, which accounts for up to 15% of coughs. First POC results were reported in patients with chronic cough at the European Respiratory Society Annual Congress in 2013.