Geoffery Burnstock's influence on the evolution of P2X3 receptor pharmacology.

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I first met Geoffery Burnstock in 1985 while working as a young post-doctoral fellow for Michael Williams at CIBA-Geigy Corporation. During that time, we were researching the role of adenosine in stroke and cardiovascular disease. These research efforts crystallized into a drug discovery program aimed at developing selective adenosine receptor agonists as cardioprotective agents. The first potent and selective A2A receptor agonist, CGS-21680, was discovered as part of this effort [1]. This high-affinity agonist was successfully radiolabeled [2] and quantitative receptor autoradiography studies demonstrated that A2A receptors were discretely localized in the rat basal ganglia [3]. These data were considered controversial at the time since other radioligand binding studies with less selective ligands had indicated a much broader expression of the A2A receptor in the central nervous system [4]. During my first discussions with Geoff, I had the opportunity to share some of these early data. Needless to say, that as a newcomer to the field, I was a bit nervous about discussing our work with such a pioneering scientist. I remember Geoff’s supportive enthusiasm for our new data and his encouragement not to let existing dogma hinder our exploration into this area of purine pharmacology. His open-minded approach and unfettered excitement for new ideas has served as an inspirational guidepost throughout my research career. Shortly after I joined the Neuroscience Discovery team at Abbott Laboratories in 1995, a new drug discovery effort targeting novel analgesic mechanisms as potential non-opioid interventions for chronic neuropathic and inflammatory pain was initiated. During an internal scientific research governance meeting, a photomicrograph from Geoff’s UCL team showing the discrete expression of P2X3 mRNA selectively localized on peripherin-positive small diameter sensory nerves was shared ahead its publication [5]. Geoff’s willingness to share these exciting data indicating a potential specific role for a single member of the emerging P2X receptor family in nociceptive neurotransmission provided sufficient evidence to initiate a specific drug discovery research effort on the nociceptive role of P2X3 receptors. In retrospect, the notion that highly selective expression of individual members of the emerging purine receptor superfamilies (e.g., A2A receptors in brain and P2X3 receptors on peripheral nerves) could drive physiologically relevant neuromodulation is striking. Furthermore, it served as the scientific foundation of much of my drug discovery research activities for the better part of two decades. Below is a brief overview of the historical development P2X3 receptor pharmacology, much of which was directly driven by Geoff’s interactions with a wide variety of academic and industrial purinergic investigators over the years. Specific questions and insights provided by Geoff on our work are highlighted to illustrate the significant impact Geoff had on our work.