Historical lessons in translational medicine: cyclooxygenase inhibition and P2Y12 antagonism.

The development of drugs that inhibit platelets has been driven by a combination of clinical insights, fundamental science, and sheer luck. The process has evolved as the days of stumbling on therapeutic gems, such as aspirin, have long passed and have been replaced by an arduous process in which a drug is designed to target a specific protein implicated in a well-characterized pathophysiological process, or so we would like to believe. The development of antiplatelet therapy illustrates the importance of understanding the mechanisms of disease and the pharmacology of the compounds we develop, coupled with careful clinical experimentation and observation and, yes, still, a fair bit of luck.

The discovery of a new class of synaptic transmitters in smooth muscle 50 years ago and amelioration of coronary artery thrombosis.

Clopidogrel and ticagrelor, antagonists to P2Y(12) receptor molecules on platelet membranes, significantly ameliorate acute myocardial infarction due to coronary artery thrombosis, the most common cause of death in the developed world. A personal account is given here of the foundational research that lead to the identification of P2Y receptors, carried out 50 years ago in the Melbourne University Zoology Department headed by Geoffrey Burnstock. In Christmas 1962, I made the serendipitous observation of large hyperpolarizing changes across the membranes of smooth muscle cells in the taenia coli of the intestine on stimulating its nerve supply. I then showed that these potentials relaxed the muscle and were not due to noradrenaline or acetylcholine, which were then the only substances known to be released from nerves. I called these non-adrenergic, non-cholinergic (NANC) terminals in the laboratory and showed that this NANC transmitter acted at receptor molecules on the muscle cells, promoting efflux of potassium ions, and so the observed potential changes. In 1968, Graeme Campbell showed that ATP relaxed the taenia coli muscle, and in 1969, David Satchell, using purine chromatography, showed that ATP was likely to be released from NANC terminals. The receptor molecules involved were shown to be exceptionally sensitive to 2-methylthio-ATP (Satchell and Macguire, 1975, J Pharmacol Exp Ther, 195, 540), and so belonged to the class P2Y receptors as designated by Abbracchio and Burnstock, with subclasses P2Y(1)-P2Y(12). The discovery of the role of P2Y(12) receptors in increasing thrombosis lead to the focused research that resulted in clopidogrel and ticagrelor.